1,2-disubstituted 1,4-dihydro-4-oxoquinoline compounds

ABSTRACT

The present invention relates to substituted 1,4-dihydro-4-oxoquinolines having antiviral activity. The substituents are present at positions 1, 2 and at least one of 5-8 positions of the quinoline ring.

RELATED PATENT APPLICATIONS

This application is a divisional application of U.S. patent application Ser. No. 09/649,596, filed Aug. 29, 2000, now U.S. Pat. No. 6,541,470.

FIELD OF THE INVENTION

This invetion related to a group of 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compounds and the use of said compounds as an antiviral agent.

BACKGROUND OF THE INVENTION

The enteroviruses, rhinoviruses and hepatovirus are three groups within the family Picornaviridae which cause a wide range of human viral disease. The enterovirus group comprises 67 distinct serotypes, including 3 strains of poliovirus, 23 group A and 6 group B coxsackieviruses, 31 echoviruses, and 4 the newer numbered enteroviruses. Enteroviruses cause a broader range disease syndrome including “summer flu”, upper respiratory illness, acute hemorrhagic conjunctivitis, hand, foot and mouth disease, myocarditis, aseptic meningitis, and poliomyelitis. Hepatitis A virus (HAV) was provisionally classified as enterovirus type 72. However, later studies have demonstrated several characteristics that distinguish HAV from other picornaviruses. It is concluded that HAV is a unique member of the family Picornaviridae, resulting in its classification into a new genus, Hepatovirus. HAV is a common cause of both sporadic and epidemic acute hepatitis in humans, produces substantial morbidity. Among the agents of viral hepatitis, HAV is most prevalent, but it is clinically less important than the hepatitis B and C virus. The clinical manifestations of HAV infection in humans can vary greatly, ranging from asymptomatic infection, commonly seen in young children, to fulminant hepatitis, which in some cases can result in death.

Human rhinovirus (HRV), which include over 100 different serotypes are the most important etiological agents of the common cold. Infection of the upper respiratory tract by members of the HRV group represents perhaps the most common viral affliction of humans, accounting for some 40 to 50% of common colds. Although HRV-induced upper respiratory illnesses often mild and self-limiting, severe disease can occur in subjects predisposed to respiratory problems, such as asthmatics. From an economic standpoint, rhinovirus infections of humans represent a significant health problem in terms of numbers of physicians' office visits, costs associated with symptomatic treatments and days lost from work and school.

Thus, infections with more than 200 different serotypes of picornavirus cause significant morbidity and mortality. The vast serotypic diversity of these viruses precludes development of vaccines for the control of human infection by these virus groups except for poliovirus and hepatitis A virus. Currently, there is no specific antiviral therapy to treat or prevent picornavirus infections.

Rotaviruses are the single most important etiologic agents of severe diarrheal illness of infant and young children world-wide. Although diarrheal diseases are one of the most common illness of infant and young children throughout the world, they assume a special significance in less developed countries, where they constitute a major cauase of mortality among the young. Rotavirus infection produces a spectrum of responses that vary from subclinical infection to mild diarrhea to a severe and occasionally fatal dehydrating illness. At present, neither a vaccine nor specific antiviral medication has been discovered for human rotavirus infections.

We have found that a group of 1,4-dihydro-4-oxoquinoline derivatives have a potent antiviral activity against picornaviruses and rotaviruses.

SUMMARY OF THE INVENTION

The present invention provides a 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compound of Formula I;

wherein each R₁ is a member independently selected from the group consisting of alkyl, cycloalkyl, phenyl, alkoxy, cycloalkyloxy, phenoxy, methylenedioxy, trifluoromethyl, halogen, OH, NO₂, NH₂, mono- or dialkylamino, pyrrolidino, piperidino, piperazino, 4-hydroxypiperazino, 4-methylpiperazino, 4-acetylpiperazino, morpholino, pyridyl, pyridyloxy, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiomorpholino, dialkylaminoalkylamino, N-alkylaminoalkyl-N-alkylamino, N-hydroxyalkyl-N-alkylamino, dialkylaminoalkoxy, acetoxy, hydroxycarbonyloxy, alkoxycarbonyloxy, hydroxycarbonylmethoxy and alkoxycarbonylmethoxy, and n is 1,2 or 3

wherein R₂ is a member selected from the group consisting of alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thiazolyl, thienyl which may be optionally substituted with alkyl or halogen, and phenyl which may be optionally substituted with up to two substituents independently selected from the group consisting of halogen, OH, alkyl, alkoxy, trifluorometlyl and acetoxy;

wherein R₃ is a member selected from the group consisting of hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN and acetyl; or

if R₂ is a phenyl group optionally substituted with halo, alkyl or alkoxy groups, R₃ may represent a bridging group between the 3rd position of the quinoline ring and said phenyl group at a position next to the ring carbon atom at which said phenyl group is directly connected to the quinoline ring, said bridging group being selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, α-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene, α-alkoxybenzylidene, 1,2-ethylidene and 1,3-propylidene; or

if R₂ is 2-thienyl, 4- or 5-alkyl-2-thienyl or N-alkylpyrrol-3-yl, R₃ may represent methylene bridge between the 3rd position of the quinoline ring and said thienyl group at the 3rd position or said pyrrolyl group at the 2nd position, and

-   -   wherein R₄ is a member selected from the group consisting of         alkyl, alkenyl, benzyl and phenyl optionally substituted with         halo, alkyl or alkoxy.

In a preferred embodiment, the compound of the present invention has Formula I-a:

wherein R₂′ is phenyl or substituted phenyl having up to two substituents independly selected from the group consisting of halo, OH, alkyl, alkoxy, trifluoromethyl and acetoxy;

R₃′ is hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkyl-sulfonyl, CN or acetyl; and

R₁, R₄ and n are as defined above.

In another embodiment, the compound of the present invention has Formula I-b:

wherein R₂″ is alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thienyl, substituted thienyl having up to two halo- or alkyl substituents, or thiazolyl; and

R₁, R₃′, R₄ and n are as defined above.

In other embodiments, if R₂ is pheny or substituted phenyl in the formula I, R₃ may be a bridge forming a fused ring system including the quinoline and benzene rings.

When the bridge is formed of a single carbon atom, the compound of the present invention is a derivative of 5,6-dihydro-11H-indeno[1,2-b]quinoline of Formula I-c:

wherein R₅ is a member independly selected from the group consisting of hydrogen, halo, alkyl and alkoxy;

R₆ and R₇ together with the carbon atom to which they are attached represent a bridge selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, α-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene and α-alkoxybenzylidene;

m is 1 or 2; and

R₁, R₄ and n are as defined above.

When the bridge is 1,2-ethylidene, the compound of the present invention is a derivative of 6,12-dihydrobenzo[c]-acridine of Formula I-d:

wherein R₁, R₄, R₅, n and m are as defined above.

When the bridge is 1,3-propylidene, the compound of the present invention is a derivative of 5,6,7,13-tetrahydro-8H-benzo[6,7]cyclohepta[1,2-b]quinoline of Formula I-e;

wherein R₁, R₄, R₅, n and m are as defined above.

In further embodiments, if R₂ is thienyl, 4- or 5-alkyl-2-thienyl or N-alkyl-pyrrol-3-yl, R₃ may be a methylene bridge forming a fused ring system including the quinoline ring and the thiophene or pyrrole ring. Thus, the compounds of the present invention include a derivative of thieno[3′, 2′:4,5]-cyclopenta[1,2-b]quinoline-5-one of Formula I-f:

wherein R₈ is hydrogen or alkyl; and

R₁, R₄ and n are as defined above.

Also included in the compounds of the present invention is a derivative of pyrrolo[3′,2′:4,5]cyclopenta[1,2-b]quinoline-5-one of Formula I-g:

wherein R₉ is alkyl, and R₁, R₄ and n are as define.

The compounds of the present invention also include a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof.

The invention also relates to a pharmaceutical composition comprising a compound of Formula I above and a pharmaceutically acceptable carrier. The pharmaceutical composition of the invention is useful in the prophylaxis and the treatment of viral infections of Picornavirus and human rotavirus.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the specification and claims, several terms are difined as follows.

Alkyl including the alkyl moiety of alkoxy refers to a straight chain or branched alkyl of up to 8, preferably 6 carbon atoms.

Alkenyl refers to an alkenyl of 2-6, preferably 3-4 carbon atoms.

Cycloalkyl refers to a cycloalkyl of 5-7 carbon atoms, preferably cyclohexyl.

Halogen refers to fluorine, chlorine or bromine.

The compounds of Formula I may be synthesized by use of known chemical reactions and procedures starting from appropriately substituted aniline II.

Generally, the synthesis of the compounds of Formula I follows either Method A or Method B. In Method A, substituted anilines II are reacted with 2-benzoylalkanoic acid ethyl ester III in the presence of polyphosphoric acid to give 2-phenyl-4-oxoquinoline derivatives (IV) followed by the reaction with R₄I in the presence of sodium hydride. Method A is applicable to the synthesis of the compounds of Formula I-a. Scheme I. Method A

In Method B, the compounds of Formula I are prepared from substituted anilines II via N-substituted isatoic anhydrides VIII.

The intermediate VIII, in turn, may be synthesized by two methods as shown in Scheme II below. Substituted anilines II are reacted with chloral hydrate and hydroxylamine to yield nitrosoacetanilide V. Cyclization of V into substituted isatins VI followed by introduction of R₄ at position 1 yields N-substituted isatins VII. N-substituted isatoic anhydrides VIII are obtained by treating VII with m-chloroperbenzoic acid(m-CPBA). Alternatively, N-substituted isatoic anhydride VIII may be prepared by reacting isatins VI with m-CPBA to produce N-unsubstituted isatoic anhydrides IX followed by introduction of R₄ at position 1. N-substituted isatins VII may also be prepared by reacting N-substituted anilines XII with oxalyl chloride followed by aluminum chloride. N-substituted anilines XII, in turn, may be prepared by acetylating substituted anilines II, reacting the resulting acetanilides X with an alkylating agent to introduce R₄ followed by deacetylation of the N-substituted acetanilides XI.

N-Substituted isatoic anhydrides VIII are used in Method B for the synthesis of the compounds of Formula I by the reaction with an appropriate ketone in the presence of n-butyl lithium and tetramethylethylenediamine (TMEDA) or in the presence of sodium hydride.

In Method B1 for the preparation of the compounds of Formula I-a, the ketone compound may be represented by the formula: R₂′C(O)CH₂R₃′, wherein R₂′ is phenyl or substituted phenyl having one or two substituents independently selected from the group consisting of halo, OH, alkyl, alkoxy, trifluoromethyl and acetoxy; and R₃′ is hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN or acetyl. The reaction involved in Method B1 is shown in Scheme III.

Similarly, Method B2 for the preparation of the compounds I-b, a ketone of the formula: R₂″C(O)CH₂R₃′, wherein R₂″ is alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thienyl, substituted thienyl having up to two halo- or alkyl substituent or thiazolyl; and R₃′ is as defined above is used. The reaction involved in Method B2 is shown in Scheme IV.

The compounds of Formula I-c wherein both R₆ and R₇ are hydrogen as well as the compounds of Formula I-d and Formula I-e are prepared by Method B3 shown in Scheme V.

Specifically, the oxo compound XIII are 1-indanones for the compounds of Formula I-c(x=1, R₆, R₇=H), 1-tetralones for the compounds Formula I-d (x=2) and 1-oxobenzosuberones (x=3), respectively.

The compounds of Formula I-c wherein R₆ and R₇ together represent oxo may be prepared by reacting the isatoic anhydride VIII with a 1,3-indandione XIV to obtain 5,10-dihydro-11H-indeno[1,2-b]quinolin-10, 11-dione compounds XV as shown in Scheme VI.

The 11-oxo compounds XV may be further manipulated using known methodoloy to obtain the compounds of Formula I-c wherein R₆ and R₇ are other than oxo. Reaction of 11-oxo compounds XV with hydroxylamine gives a corresponding oxime. Reaction of oxime with an alkylating agent in the presence of sodium hydride gives a 11-alkoxyimino compound. The oxime further gives a 11-alkanoylamino compound by acylation with an acylating agent such as acetyl anhydride in a reducing atomosphere. Saponification of 11-alkanoylamino compound leads to 11-amino compound.

The 11-oxo compounds XV may be converted into a 11-hydroxy compound by the reaction with sodium borohydride. Reaction of 11-oxo compounds XV with alkyl- or phenyl magnesium halide leads to a 11-hydroxy-11-alkyl or phenyl devivative. The hydroxy group at position 11 may further be alkylated in the presence of sodium hydride to give a 11-alkoxy-11-alkyl or phenyl derivative. The hydroxy group at position 11 may be removed by the reaction with sodium iodide and trimethylsilyl chloride to give 11-alkyl or phenyl derivative.

Finally, the compounds of Formula I-f and Formula I-g may be prepared by Method B4 as shown in Scheme VII. The compounds of Formula I-f are prepared by the reaction of isatoic anhydride VIII with 4,5-dihydro-6H-cyclopenta[b]-thiophen-6-one XVI in the presence of n-BuLi and TMEDA. Reaction of isatoic anhydride VIII with 1-methyl-5,6-dihydro-4H-cyclopenta[b]pyrrol-4-one XVII in the presence of n-BuLi and TMEDA gives the compounds of Formula I-g.

EXAMPLES

The following examples are given for illustrative purposes only. Part A.

Example 1 1-Ethyl-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline(Compound A37)

Step 1. 2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline

To polyphosphoric acid (1.5 g) heated to 160° C. were added dropwise a solution of 4-isopropylaniline(0.5 g, 3.6 mmol) and ethyl 2-benzoylpropionate (1.52 g, 7.3 mmol) in ethanol with stirring. The mixture was stirred at 160° C. for 3 hours. After cooling, a cold solution of 10% hydrochloric acid was added to the mixture. The resulting precipitate was recovered by filtration, dissolved in methanol and treated with active carbon. After evaporating in vacuo, the residue was recrystallized from ethyl acetate to give the title compound in a yield of 81%. ¹H-NMR(DMSO-d₆) δ 1.28 (6H, d, CH(CH ³ )₂), 2.0 (3H, s, CH₃), 3.07 (1H, septet, CH), 7.61 (5H, s, Ar—H), 7.6-7.7 (2H, m, H-7,8), 8.13 (1H, s, H-5), 12.67 (1H, s, NH)

Step 2. 1-ethyl-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline

To a solution of 0.28 g(1 mmol) of 2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquiline in DMF (10 mL) were added potassium carbonate(3 mmol) and ethyl iodide(5 mmol). The mixture was heated with stirring for 4.5 hours. After removing the solvent, the residue was dissolved in water and extracted with ethyl acetate twice. The combined organic layers were washed with water and then saturated sodium chloride solution followed by drying with sodium sulfate and evaporation in vacuo. The residue was purified by silica gel-column chromatography(hexane:ethyl acetate=2:1) to yield the title compound. ¹H-NMR (CDCl₃) δ 1.1-1.4 (3H, t, NCH₂ CH ³ ), 1.3-1.5 (6H, d, CH(CH ³ )₂), 1.8 (3H, s, CH₃), 2.7-3.4 (1H, m, CH), 3.8-4.2 (2H, q, NCH₂), 7.1-7.8 (7H, m, Ar—H), 8.3-8.6 (1H, s, H-5).

Example 2 1-Ethyl-2-(3-methyl-4-methoxyphenyl)-3,5-dimethyl-6-isobutoxy-1,4-dihydro-4-oxoquinoline (Compound A191)

Step 1. 3′-Methyl-4′-methoxyacetophenone

To an ice-cooled solution of 3′-methyl-4′-hydroxyacetophenone (15 g, 100 mmol) in 100 mL of DMF was added 60% sodium hydride (2.4 g, 101 mmol) under argon atmosphere with stirring. After 30 minutes, methyl iodide(7.5 mL, 120 mmol) was added to the solution and allowed to react overnight at room temperature with stirring. The reaction mixture was evaporated to remove the solvent. The residue was dissolved in water and extracted with diethyl ether thrice. The combined organic layers were sequentially washed with water and saturated sodium chloride solution, dried with sodium sulfate and distilled under reduced pressure (116° C./0.2 mmHg) to obain the title compound in a yield of 71%. ¹H-NMR (CDCl₃) δ 2.24 (3H, s, CH₃), 2.54 (3H, s, COCH₃), 3.90 (3H, s, OCH₃), 6.84 (1H, d, H-5′), 7.77 (1H, dd, H-2′), 7.82 (1H, dd, H-6′)

Step 2. 3-Methyl-4-methoxybenzoic Acid

To a suspension of bleaching powder(72 g, 500 mmol) in 270 mL of water was added a solution of potassium hydroxide (14 g, 250 mmol) and potassium carbonate (50.5 g 365 mmol) in 150 mL of water. The suspension was stirred for 2 hours under sealing and the filtered to remove precipitated calcium salt. The precipitate was washed with a small amount of water and washing was combined with the above filtrate. To the filtrate was added 3′-methyl-4′-methoxyacetophenone (27.3 g, 166 mmol) while stirring vigorously. The mixture was stirred overnight at room temperature. After adding sodium bisulfate (17.8 g 171 mmol), the reaction mixture was washed twice with diethyl ether. The aqueous layer was acidified with hydrochloric acid. The resulting crystals were filtered off followed by drying under reduce pressure to yield the title compound.

¹H-NMR (CDCl₃) δ 2,18 (3H, s, CH₃), 3.89 (3H, s, OCH₃), 7.02 (1H, d, H-5), 7.74 (1H, dd, H-2), 7.81 (1H, dd, H-6)

Step 3. Ethyl 3-methyl-4-methoxybenzoate

A solution of 3-methyl-4-methoxybenzoic acid (20 g,120 mmol) and ethyl orthoformate (19.6 g 132 mmol) in 300 mL of ethanol was refluxed overnight with the addition of concentrated sulfuric acid (4 mL) followed by evaporation in vacuo to remove the solvent. The residue was dissolved in water. The solution was made alkaline with sodium carbonate and extracted thrice with chloroform. The combined organic layers were sequentially washed with saturated sodium carbonate solution, water and saturated sodium chloride solution, dried with sodium sulfate and distilled under reduced pressure (185-190° C./0.3 mmHg) to give the title compound. ¹H-NMR (CDCl₃) δ 1,38 (3H, t, CH₂ CH ³ ), 2.23 (3H, s, 3-CH₃), 3.87 (3H, s, OCH₃), 4.34 (2H, dq, CH ² CH₃), 6.82 (1H, d, H-5), 7.83 (1H, dd, H-2), 7.89 (1H, dd, H-6)

Step 4. Ethyl 2-(3-methyl-4-methoxybenzoyl)propionate

To a mixture of ethyl 3-methyl-4-methoxybenzoate (24.8 g 128 mmol) and 60% sodium hydride (3.1 g, 128 mmol) under argon atmosphere was added dropwise a solution of ethyl propionate (6.5 g, 64 mmol) in 200 mL of n-butyl ether with stirring while keeping the inner temperature at 90-100° C. Stirring was continued for additional 3 hours at 130° C. After cooling to room temperature, excessive sodium hydride in the reaction mixture was decomposed with ethanol. After the addition of water, the reaction mixture was neutrallized with hydrochloric acid and extracted with diethyl ether thrice. The combined organic layers were sequentially washed with saturated sodium carbonate solution, water and saturated sodium chloride solution followed by drying with sodium sulfate. Distillation of the organic layers under reduced pressure (185-190° C./0.3 mmHg) gave the title compound. ¹H-NMR (CDCl₃) δ 1.19 (3H, t, CH₂ CH ³ ), 1.47 (3H, d, CHCH ³ ), 2,25 (3H, s, 3′-CH₃), 3.90 (3H, s, OCH₃), 4.15 (2H, dq, CH ² CH₃), 4.34 (1H, q, CH), 6.86 (1H, d, H-5′), 7.80 (1H, dd, H-2′), 7.86 (1H, dd, H-6′)

Step 5. 3-Methyl-4-isobutoxynitrobenzene

Isobutyl alcohol (1.5 g, 5 mmol) was dissolved in anhydrous DMF under argon atmosphere and cooled to −15° C. To this solution was added 60% sodium hydride (0.37 g, 15.5 mmol) with stirring followed by 2-nitro-5-fluorotoluene (2 g, 13 mmol) after 30 minutes. The mixture was stirred for additional 2 hours at the same temperature followed by distilling off DMF. The residue was diluted with water and extracted with chloroform thrice. The combined organic layers were was sequentially washed with water and saturated sodium chloride solution, dried with sodium sulfate and purified by silica gel-column chromatography (chloroform) to give the titel compound. ¹H-NMR (CDCl₃) δ 1.07 (6H, d, (CH ³ ) ₂), 2.16 (1H, septet, CH), 2.29 (3H, s, 3-CH₃), 3.83 (2H, d, CH₂), 6.82 (1H, d, H-5), 8.04 (1H, d, H-2), 8.08 (1H, dd, H-6)

Step 6. 3-methyl-4-isobutoxyaniline

To a solution of 3-methyl-4-isobutoxynitrobenzene (2.72 g, 13 mmol) in ethanol (25 mL) were added iron powder (13 g), water (1.5 mL) and concentrated hydrochloric acid (0.13 mL). The mixture was refluxed for 1 hour and then filtered while hot. The filtrate was concentrated in vacuo. The residue was dissolved in chloroform followed by drying with sodium sulfate. Removal of chloroform by evaporation gave the title compound. ¹H-NMR (CDCl₃) δ 1.01 (6H, d, CH(CH ³ )₂), 2.06 (1H, septet, CH), 2.17 (3H, s, 3-CH₃), 3.33 (2H,brs,NH₂), 3.63 (2H, d, CH₂), 6.53 (1H, d, H-2), 6.63 (1H, d, H-5), 6.67 (1H, dd, H-6)

Step 7. 2-(3-Methyl-4-methoxyphenyl)-3,5-dimethyl-6-isobutoxy-1,4-dihydro-4-oxoquinoline

To polyphosphoric acid (3 g) heated to 160° C. was added dropwise a solution of ethyl 2-(3-methyl-4-methoxybenzoyl) propionate (3,4 g,13.4 mmol) and 3-methyl-4-isobutoxyaniline (1.2 g, 6.7 mmol) in ethanol (2 mL) with stirring.

The mixture was stirred for additional 1 hour and allowed to cool to room temperature. An amount of crashed ice and 20% hydrochloric acid were added to the reaction mixture and extracted with chloroform. The organic layer was washed sequentially with saturated sodoium carbonate solution, water and saturated sodium chloride solution followed by drying with sodium sulfate. The residue resulting from evaporation of chloroform was roughly purified by silica gel-column chromatography(chloroform: acetone=20:1).

The title compound was obtained by crystallizing the crude product from diethyl ether. ¹H-NMR (CDCl₃) δ 1.08 (6H, d, CH(CH ³ )₂), 1.87 (3H, s, 3-CH₃), 2.07 (3H, s, 3′-CH₃), 2,14 (1H, septet, CH), 2.91 (3H, s, 5-CH₃), 3.75 (2H, d, CH₂), 3.76 (3H, s, OCH₃), 6.65 (1H, s, H-5′), 7.11 (1H, d, H-2′), 7.13 (1H, dd, H-6′), 7.21 (1H, d, H-8), 7.48 (1H, d, H-7), 9.78 (1H, s, NH)

Step 8. 1-Ethyl-2-(3-methyl-4-methoxyphenyl)-3,5-dimethyl-6-isobutoxy-1,4-dihydro-4-oxoquinoline

2-(3-Methyl-4-methoxyphenyl)-3,5-dimethyl-6-isobutoxy-1,4-dihydro-4-oxoquinoline(0.18 g, 0.5 mmol) was dissolved in anhydrous DMF under argon atmosphere.

To the solution were added while ice cooling and stirring 60% sodium hydride (0.013 g, 0.54 mmol). After 30 minutes, ethyl iodide (0.12 g, 0.75 mmol) was added to the mixture followed by stirring overnight. After removing DMF by distillation, water was added to the reaction mixture followed by extraction with ethyl acetate thrice. The combined organic layers were washed sequentially with water and saturated sodium chloride solution, dried with sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel-column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound. ¹H-NMR (CDCl₃) δ 1.08 (6H, d, CH(CH ³ )₂), 1.19 (3H, t, CH₂ CH ³ ), 1.77 (3H, s, 3-CH₃), 2.15 (1H, septet, CH), 2.28 (3H, s, 3′-CH₃), 2.98 (3H, s, 5-CH₃), 3.78 (2H, d, OCH₂), 3.91 (3H, s, OCH₃), 3.96 (3H, q, CH ² CH₃), 6.93 (1H, d, H-5′), 7.03 (1H, d, H-2′), 7.05 (1H, dd, H-6′), 7.25 (1H, d, H-8), 7.33 (1H, d, H-7)

Example 3 1-(4-chlorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline(Compound A324)

Step 1. 4-Isopropylacetanilide

To a solution of 4-isopropylaniline (5.2 g, 38 mmol) in acetic acid was added while ice-cooling and stirring acetic anhydride (4 ml, 42 mmol). After stirring at room temperature overnight, the reaction mixture was poured into ice water. The resulting precipitate was filtered off, washed with water and then dried under reduced pressure to give the title compound. ¹H-NMR (CDCl₃) δ 1.22 (6H, d, CH(CH ³ )₂), 2.15 (3H, s, NHCOCH ³ ), 2.87 (1H, septet, CH), 7.28 (4H, d, Ar—H)

Step 2. 1-(4-Chlorophenyl)-4-isopropylacetanilide

Under argon atmosphere, a mixture of 4-isopropyl-acetanilide (2.5 g, 5 mmol), 4-chlorobromobenzene (2.97 g, 15.5 mmol), cupric iodide (2.95 g, 15.5 mmol) and potassium carbonate (1.5 g, 10.9 mmol) was heated at 160-180° C. for 30 hours followed by allowing to cool. The reaction mixture was diluted with water and diethyl ether and filtered to remove insolubles. The organic layer was separated, washed with water and saturated sodium chloride solution and dried with sodium sulfate. After removing the solvent, the residue was purified by silica gel-column chromatography (chloroform) to yield the title compound.

¹H-NMR (CDCl₃) δ 1.25 (6H, d, CH(CH ³ )₂), 2.05 (3H, s, NCOCH₃), 2.92 (4H, septet, CH), 7.15-7.28 (8H, m, Ar—H)

Step 3. 1-(4-Chlorophenyl)-4-isopropylaniline

A solution of 1-(4-chlorophenyl)-4-isopropylacetanilide (2.91 g, 10 mmol) in ethanol (35 mL) was mixed with 15 mL of concentrated hydrochloric acid. The mixture was refluxed overnight and evaporated to remove ethanol. The resulting residue was diluted with water and made alkaline with sodium hydroxide. This solution was extracted with diethyl ether twice. The combined organic layers were sequentially washed with water and saturated sodium chloride solution, dried with sodium sulfate and evaporated in vacuo to give the title compound. ¹H-NMR (CDCl₃) δ 1.24 (6H, d, CH(CH ³ )₂), 2.87 (1H, septet, CH), 5,59 (1H, s, NH), 6.91-7.19 (8H, m, Ar—H)

Step 4. 1-(4-Chlorophenyl)-5-isopropylisatin

To a solution of 1-(4-chlorophenyl)-4-isopropylaniline (2.29 g, 9.3 mmol) in dry benzene under argon atmosphere was added oxalyl chloride (1.42 mL, 16.3 mmol) while ice cooling and stirring. The mixture was stirred at room temperature for additional 2 hours followed by evaporation under reduced pressure to remove excessive oxalyl chloride. The residue was dissolved in 1,2-dichloroethane. To this solution was added under argon atmosphere anhydrous aluminum chloride (1.28 g, 9.6 mmol) in portions. The mixture was stirred at room temperature overnight and then gradually poured into ice-water (40 mL) containing 10 mL of 2N hydrochloric acid solution. The organic phase was separated, sequentially washed with 2N sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried with sodium sulfate and evaporated under reduced pressure to remove 1,2-dichloroethane. The title compound was obtained by crystalizing the residue from diethyl ether, ¹H-NMR (CDCl₃) δ 1.24 (6H, d, CH(CH ³ )₂, 2,92 (1H, septet, CH), 6.82 (1H, d, H-7), 7.36-7.55 (4H, m, Ar—H), 7.42 (1H, dd, H-6), 7.59 (1H, d, H-4)

Step 5. 1-(4-Chlorophenyl)-6-isopropylisatoic anhydride

A solution of 1-(4-chlorophenyl)-5-isopropylisatin (1.5 g, 5.0 mmol) in methylene chloride was added dropwise to a solution of m-chloroperbenzoic acid (907 mg, 5.3 mmol) in methylene chloride. The mixture was stirred at room temperature for 2 hours and then poured into ice-water containing 3 equivalents of sodium hydrogen sulfite followed by extraction with methylene chloride. The methylene chloride layer was sequentially washed with 1% sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried with sodium sulfate and then evaporated to remove methylene chloride. The title compound was obtained by crystallizing the residue from diethyl ether. ¹H-NMR (CDCl₃) δ 1.24 (6H, d, CH(CH ³ )₂), 2.95 (1H, septet, CH), 6.49 (1H, d, H-8), 6.98 (1H, dd, H-7), 7.26-7.60 (4H, m, Ar—H), 8.03 (1H, d, H-5)

Step 6. 1-(4-Chlorphenyl)-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline

Tetramethylethylenediamine (1.05 mL, 6.94 mmol) was gradially added with stirring into a solution of 1.55M hexane solution of n-butyl lithium (4.5 mL, 6.94 mmol) under argon atmosphere. Then a solution of propiophenone (936 mg, 6.94 mmol) in anhydrous THF was aded to the mixture while ice cooling and stirring. The reaction mixture was stirred for additional 3 hours at room temperatured and then ice-cooled.

To this was added dropwise a solution of 1-(4-chlorophenyl)-6-isopropylisatoic anhydride (1.10 g, 3.47 mmol) in anhydrous THF. The reaction mixture was stirred overnight at room temperature and diluted with saturated ammonium chloride. The organic layer was separated and concentrated in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel-column chromatography (chloroform:acetone=20:1) followed by crystallization from diethyl ether to give the title compound. ¹H-NMR (CDCl₃) δ 1.31 (6H, d, CH(CH ³ )₂), 1.91 (3H, s, CH₃), 3.05 (1H, septet, CH), 6.67 (1H, d, H-8), 7.01-7.28 (9H, m, Ar—H), 7.33 (1H, dd, H-7), 8.39 (1H, d, H-5)

Example 4 1,2-Diphenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline (Compound A320)

Step 1. 4-Isopropylisonitrosoacetanilide

A solution of chloral hydrate (9.0 g, 54 mmol) and anhydrous sodium sulfate (57 g) in 190 mL of water was heated to 60° C. . To this solution were added a warmed solution (70° C.) of 4-isopropylaniline (6.8 g, 50 mmol) and concentrated hydrochloric acid (4.3 mL, 52 mmol) in 150 mL of water followed by a warmed solution of hydroxylamine hydrochloride (11.0 g, 158 mmol) in 50 mL of water. The resulting solution was heated to boiling temperature over 40 minutes and then refluxed for 2 minutes. After cooling with tap water, the resulting precipitate was filtered off, washed with cold water and dried under reduced pressure to give the title compound. ¹H-NMR (CDCl₃) δ 1.21 (6H, d, CH₃), 2.96 (1H, septet, CH), 6.72 (1H, brs, OH), 7.18 (2H, d, H-3.5), 7.47 (2H, d, H-2,6), 7.58 (1H, s, CH═N), 8.34 (1H, s, NH)

Step 2. 5-Isopropylisatin

30 mL of concentrated sulfuric acid was heated to 50° C. To this was added 4-isopropylnitrosoacetanilide (8.4 g, 41 mmol) in portions while maintaing the inner temperature at 60-70° C. . The reaction mixture was heated at 80° C. for 10 minutes with stirring, allowed to cool to room temperature and poured into ice(about 300 g). The resulting precipitate was filtered off, washed with cold water and dried under reduced pressure to give the title compound. ¹H-NMR (CDCl₃) δ 1.21 (6H, d, CH₂), 2.96 (1H, septet, CH), 7.10 (1H, d, H-8), 7.67 (1H, d, H-7), 7.74 (1H, d, H-5), 11.66 (1H,brs,NH)

Step 3. 1-Phenyl-5-isopropylisatin

A solution of 5-isopropylisatin (500 mg, 2.6 mmol), bromobenzene(10 mmol) and cupric iodide (420 mg, 5.3 mmol) in DMF was heated at 180° C. for 5.5 hours with stirring. The reaction mixture was filtered while hot and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform followed by drying with sodium sulfate. The chloroform solution was evaporated to remove the solvent and the residue was purified by silica gel-chromatography (chloroform) to give the title compound. ¹H-NMR (CDCl₃) δ 1.25 (6H, d, CH(CH ³ )₂, 2.92 (1H, septet, CH), 6.83 (1H, d, H-7), 7.38-7.57 (6H, m, Ar—H), 7.59 (1H, d, H-4)

Steps 4 and 5. 1,2-Diphenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline

The title compound was prepared from 1-phenyl-5-isopropylisatin in a manner analogous to steps 5 and 6 of Example 3. ¹H-NMR (CDCl₃) δ 1.31 (6H, d, CH(CH ³ )₂), 1.93 (3H, s, CH₃), 3.05 (1H, septet, CH), 6.69 (1H, d, H-8), 7.04-7.33 (1H, m, Ar—H)

Example 5 1-Methyl-2-phenyl-3-ethoxycarbonyl-6-isopropyl-1,4-dihydro-4-oxoquinoline (Compound A50)

Step 1. 6-Isopropylisatoic Anhydride

To a solution of m-chloroperbenzoic acid (5 g, 28.5 mmol) in THF (20 mL) was added dropwise a solution of 5-isopropylisatin (2.7 g, 14.3 mmol) in THF (50 mL) under ice-cooling and stirring. After stirring for additional 3 hours under ice-cooling, the reaction mixture was treated with 10% sodium hydrogen sulfite solution (60 mL) to decompose excessive m-CPBA. The solution was poured into ice water (200 mL) and extracted with ethyl acetate several times. The combined organic layers were washed with water and saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuo. The resulting residue was crystallized from diethyl ether to give the title compound.

¹H-NMR (CDCl₃) δ 1.23 (6H, d, CH(CH ³ )₂), 2.88 (1H, septet, CH), 6.95 (1H, d, H-7), 7.43 (1H, dd, H-6), 7.47 (1H, d, H-4)

Step 2. 1-Methyl-6-isopropylisatoic Anhydride

To a suspension of 60% sodium hydride (0.54 g, 13.4 mmol) in anhydrous DMF(30 mL), 6-isopropylisatoic anhydride (2.5 g, 12.2 mmol) was added at room temperature under argon atmosphere with stirring. After 30 minutes, methyl iodide (1.9 g, 13.4 mmol) was added to the reaction mixture followed by stirring at room temperature overnight. The reaction mixture was evaporated to remove DMF and extracted with chloroform. The extract was washed with water and saturates sodoium chloride solution, dried with sodium sulfate and evaporated in vacuo to dryness. The titled compound was obtained by crystalling the residue from diethyl ether. ¹H-NMR (CDCl₃) δ 1.28 (6H, d, CH(CH ³ )₂), 2.99 (1H, septet, CH), 3.57 (3H, s, N—CH₃), 7.12 (1H, d, H-8), 7.64 (1H, dd, H-7), 8.01 (1H, d, H-5)

Step 3. 1-Methyl-2-phenyl-3-ethoxycarbonyl-6-isopropyl-1,4-dihydro-4-oxoquinoline

To a suspension of 60% sodium hydride (0.06 g, 1.5 mmol) in anhydrous DMF (10 mL) was added ethyl benzoylacetate (0.29 g, 1,5 mmol) at room temperature under argon atmosphere with stirring. After 30 minutes, 1-metyl-6-isopropylisatoic anhydride (0.33 g, 1,5 mmol) was added to the mixture at 60° C. with stirring. The temperature was raised to 120° C. over 1 hour. The stirring was continued at the same temperature for additional 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel-chromatography (chloroform: acetone=9:1) followed by crystallization from diethyl ether to obtain the desired compound. ¹H-NMR (CDCl₃) δ 0.93 (3H, t, CH₂ CH ³ ), 1.35 (6H, d, CH(CH ³ )₂, 3.09 (1H, septet, CH), 3.98 (2H, q, OCH₃), 7.39-7.41 (2H, m,H-2′,6′), 7.47-7.50 (4H, m, H-3′,4′,5′,8′), 7.61 (1H, dd, H-7), 8.40 (1H, d, H-5)

Example 6 1-Ethyl-2-(2-furyl)-6-isopropyl-1,4-dihydro-4-oxoquinoline (Compound A304)

Step 1. 1-Ethyl-6-isopropylisatoic Anhydride

6-Propylisatoic anhydride was reacted with ethyl iodide in the presence of sodium hydride in a manner analogous to step 2 of Example 5 to prepare the title compound. ¹H-NMR (CDCl₃) δ 1.28 (6H, d, CH(CH ³ )₂), 1.38 (3H, t, CH₂ CH ³ ), 2.99 (1H, septet, CH), 4.13 (2H, q, NCH₂), 7.14 (1H, d, H-8), 7.64 (1H, dd, H-7), 8.01 (1H, d, H-5)

Step 2. 1-Ethyl-2-(2-furyl)-6-isopropyl-1,4-dihydro-4-oxoquinoline

To a 1.6M solution of n-butyl lithium in hexane (1,38 mL, 2,2 mmol) was added tetramethylethylenediamine (0.3 mL, 2,2 mmol) under argon atmosphere at room temperature with stirring. Then 2-acetylfuran (242 mg, 2,2 mmol) in anhydrous THF was added dropwise to the mixture under ice cooling followed by stirring for 1 hour. To this mixture was added 1-ethyl-6-isopropylisatoic anhydride (250 mg, 1.1 mmol) in anhydrous THF. After stirring at room temperature overnight, the reaction mixture was diluted with saturated aqueous solution of ammonium chloride. The resulting organic layer was separated and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and then washed with saturated sodium chloride solution followed by drying with sodium sulfate. After removing ethyl acetate by evaporation in vacuo, the residue was subjected to preparative TLC(n-hexane:ethyl acetate=2:1) to separate the title compound followed by crystallization from diethyl ether. ¹H-NMR (CDCl₃) δ 1.33 (6H, d, CH(CH ³ )₂), 1.55 (3H, t, CH₂ CH ³ ), 3.08 (1H,septet,CH), 4.17 (2H, q, NCH₂), 6.48 (1H, s, H-3), 6.56-6.58 (1H, m, furan H-4′), 6.76 (1H, dd, furan H-5′), 7.54 (1H, d, H-8), 7.59 (1H, dd, H-7), 7.63 (1H, dd, furan H-3′), 8.34 (1H, d, H-5)

The following compounds have been produced in a manner analogous to that described in the preceding examples.

TABLE I Com- pound m.p. No. R₁ X R₃′ R₄ (° C.) A12 6-Br H H CH₃ 166-168 A13 5-OH H CH₃ CH₃ 282-283 A14 6-OH H CH₃ CH₃ >300  A15 7-OH H CH₃ CH₃ >300  A16 8-OH H CH₃ CH₃ 240-242 A17 6-CH₃ H H C₂H₅ 169-170 A18 6-CH₃ H CH₃ C₂H₅ 167-170 A19 5-CH₃O H CH₃ CH₃ 141-142 A20 6-CH₃O H CH₃ CH₃ 154-156 A21 6-CH₃O 3-CH₃ H C₂H₅ 193-194 4-CH₃O A22 6-CH₃O 3-CH₃ H C₂H₅ 140-142 4-i-C₃H₇O A23 6-CH₃O 3-CH₃ H C₂H₅ 144-145 4-i-C₄H₉O A24 7-CH₃O H CH₃ CH₃ 188-191 A25 8-CH₃O H CH₃ CH₃ 131-133 A26 6-C₂H₅ H CH₃ C₂H₅ 151-154 A27 6-C₂H₅O H H CH₃ 156-159 A28 6-C₂H₅O H CH₃ C₂H₅ 165-167 A29 6-C₃H₇ H CH₃ CH₃ 127 A30 6-C₃H₇ R CH₃ C₂H₅ 133-134 A31 6-C₃H₇O H CH₃ CH₃ 162-163 A32 6-C₃H₇O H CH₃ C₂H₅ 136-140 A33 5-i-C₃H₇ H CH₃ CH₃ 153-155 A34 5-i-C₃H₇ H CH₃ C₂H₅ 144 A35 6-i-C₃H₇ H H CH₃ 140-141 A36 6-i-C₃H₇ H CH₃ CH₃ 197-199 A37 6-i-C₃H₇ H CH₃ C₂H₅ 159-165 A38 6-i-C₃H₇ H CH₃ i-C₃H₇ 184-186 A39 6-i-C₃H₇ H CH₃O CH₃ 169-173 A40 6-i-C₃H₇ H C₂H₅ CH₃ 172 A41 6-i-C₃H₇ H C₂H₅ C₂H₅ 129-130 A42 6-i-C₃H₇ H C₃H₇ CH₃ 102-103 A43 6-i-C₃H₇ H C₃H₇ C₂H₅ oil A44 6-i-C₃H₇ H i-C₃H₇ CH₃ 177-179 A45 6-i-C₃H₇ H i-C₃H₇ C₂H₅ 148 A46 6-i-C₃H₇ H C₄H₉ CH₃ 136-137 A47 6-i-C₃H₇ H C₄H₉ C₂H₅ oil A48 6-i-C₃H₇ H C₆H₁₃ CH₃ 84-86 A49 6-i-C₃H₇ H C₆H₁₃ C₂H₅ oil A50 6-i-C₃H₇ H C₂H₅OCO CH₃ 164-165 A51 6-i-C₃H₇ H CH₃SO₂ CH₃ 245-247 A52 6-i-C₃H₇ H CN CH₃ 250-251 A53 6-i-C₃H₇ H CH₃CO CH₃ 169-171 A54 6-i-C₃H₇ 3-Cl CH₃ C₂H₅ 159-160 A55 6-i-C₃H₇ 4-Cl H CH₃ 149-152 A56 6-i-C₃H₇ 4-Cl H C₂H₅ 172-173 A57 6-i-C₃H₇ 4-Cl CH₃ CH₃ 231-232 A58 6-i-C₃H₇ 4-Cl CH₃ C₂H₅ 204-205 A59 6-i-C₃H₇ 3-F CH₃ CH₃ 263 A60 6-i-C₃H₇ 3-F CH₃ C₂H₅ 174-175 A61 6-i-C₃H₇ 3,4-diCl H CH₃ 207-210 A62 6-i-C₃H₇ 3,4-diCl CH₃ CH₃ 268-270 A63 6-i-C₃H₇ 3,4-diCl H C₂H₅ 160-162 A64 6-i-C₃H₇ 3,4-diCl CH₃ C₂H₅ 197-198 A65 6-i-C₃H₇ 3,4-diF CH₃ CH₃ 278-279 A66 6-i-C₃H₇ 3,4-diF CH₃ C₂H₅ 194-196 A67 6-i-C₃H₇ 3-CF₃ CH₃ CH₃ 200-201 A68 6-i-C₃H₇ 3-CF₃ CH₃ C₂H₅ 179 A69 6-i-C₃H₇ 4-CF₃ CH₃ CH₃ >300  A70 6-i-C₃H₇ 4-CF₃ CH₃ C₂H₅ 218-219 A71 6-i-C₃H₇ 2-OH H CH₃ >300  A72 6-i-C₃H₇ 3-OH H CH₃ 248-249 A73 6-i-C₃H₇ 4-OH H CH₃ >300  A74 6-i-C₃H₇ 4-OH CH₃ CH₃ >300  A75 6-i-C₃H₇ 2-CH₃ CH₃ C₂H₅ 157-159 A76 6-i-C₃H₇ 3-CH₃ CH₃ CH₃ 181-183 A77 6-i-C₃H₇ 3-CH₃ CH₃ C₂H₅ 140-144 A78 6-i-C₃H₇ 3-CH₃O CH₃ C₂H₅ 130-132 A79 6-i-C₃H₇ 4-CH₃ CH₃ CH₃ 180-181 A80 6-i-C₃H₇ 4-CH₃ CH₃ C₂H₅ 171-172 A81 6-i-C₃H₇ 4-CH₃O CH₃ CH₃ 177-178 A82 6-i-C₃H₇ 4-CH₃O CH₃ C₂H₅ 193-196 A83 6-i-C₃H₇ 4-CH₃O CH₃ C₃H₇ 199-202 A84 6-i-C₃H₇ 4-C₂H₅ CH₃ CH₃ 193-194 A85 6-i-C₃H₇ 4-C₂H₅ CH₃ C₂H₅ 148-150 A86 6-i-C₃H₇ 4-C₂H₅O CH₃ CH₃ 169-170 A87 6-i-C₃H₇ 4-C₂H₅O CH₃ C₂H₅ 173-175 A88 6-i-C₃H₇ 4-C₃H₇ CH₃ CH₃ 181-183 A89 6-i-C₃H₇ 4-C₃H₇ CH₃ C₂H₅ 88-91 A90 6-i-C₃H₇ 4-C₃H₇O CH₃ CH₃ 164-166 A91 6-i-C₃H₇ 4-C₃H₇O CH₃ C₂H₅ 125-127 A92 6-i-C₃H₇ 4-C₃H₁₁ CH₃ CH₃ 159-160 A93 6-i-C₃H₇ 4-C₅H₁₁ CH₃ C₂H₅ 110-113 A94 6-i-C₃H₇ 4-C₅H₁₁O CH₃ CH₃ 137-138 A95 6-i-C₃H₇ 4-C₅H₁₁O CH₃ C₂H₅ 255-257 A96 6-i-C₃H₇ 3-CH₃ H CH₃ 248-250 4-OH A97 6-i-C₃H₇ 3-CH₃ H CH₃ 209-210 4-CH₃O A98 6-i-C₃H₇ 3-CH₃ H C₂H₅ 128-129 4-CH₃O A99 6-i-C₃H₇ 3-CH₃ H CH₃ 134-135 4-C₂H₅O A100 6-i-C₃H₇ 3-CH₃ H CH₃ 130-131 4-i-C₃H₇O A101 6-i-C₃H₇ 3-CH₃O H CH₃ 293-295 4-OH A102 6-i-C₃H₇ 3-C₂H₅ H CH₃ 155-157 4-CH₃O A103 6-i-C₃H₇ 3-C₂H₅ H CH₃ 147-150 4-i-C₃H₇O A104 6-i-C₃H₇ 3-C₂H₅ H CH₃ 149-153 4- CH₃COO A105 6-i-C₃H₇ 3-i-C₃H₇ H CH₃ 180-182 4-CH₃O A106 6-i-C₃H₇ 2,3-diCH₃ CH₃ CH₃ 185-187 A107 6-i-C₃H₇ 2,4-diCH₃ CH₃ CH₃ 151-152 A108 6-i-C₃H₇ 2,4-diCH₃ CH₃ C₂H₅ 121 A109 6-i-C₃H₇ 2,5-diCH₃ CH₃ CH₃ 143-145 A110 6-i-C₃H₇ 3,4-diCH₃ CH₃ CH₃ 154-156 A111 6-i-C₃H₇ 3,4-diCH₃ CH₃ C₂H₅ 119-121 A112 6-i-C₃H₇ 3,5-diCH₃ CH₃ C₂H₅ 151-155 A113 6-i-C₃H₇ 3-OH CH₃ CH₃ 295 4-CH₃ A114 6-i-C₃H₇ 3-OH CH₃ CH₃ 227-228 4-CH₃O A115 6-i-C₃H₇ 3-CH₃ CH₃ C₂H₅ 158-160 4-CH₃O A116 6-i-C₃H₇ 3-CH₃ C₂H₅OCO C₂H₅ 179-180 4-CH₃O A117 6-i-C₃H₇ 3-CH₃O CH₃ CH₃ 166 4-CH₃ A118 6-i-C₃H₇ 3-CH₃O CH₃ C₂H₅ 164-166 4-CH₃ A119 6-i-C₃H₇O 3-CH₃ H C₂H₅ 177-178 4-CH₃O A120 6-i-C₃H₇O 3-CH₃ H C₂H₅ 123-124 4-i-C₃H₇O A121 7-i-C₃H₇ H CH₃ CH₃ 156-157 A122 7-i-C₃H₇ H CH₃ C₂H₅ 142-144 A123 7-i-C₄H₉O H CH₃ CH₃ 179-182 A124 6-C₄H₉ H CH₃ CH₃ 140 A125 6-C₄H₉ H CH₃ C₂H₅ 85-86 A126 6-C₄H₉O H CH₃ CH₃ 126-128 A127 6-C₄H₉O H CH₃ C₂H₅ 136-138 A128 6-i-C₄H₉ H CH₃ C₂H₅ 121-125 A129 6-i-C₄H₉O H CH₃ CH₃ oil A130 6-i-C₄H₉O H CH₃ C₂H₅ 106-107 A131 6-i-C₄H₉O H CH₃ 2- 97-101 butenyl A132 6-i-C₄H₉O H CH₃ benzyl 178-181 A133 6-i-C₄H₉O 3-CH₃ H CH₃ 167-168 4-CH₃O A134 6-i-C₄H₉O 3-CH₃ H C₂H₅ 169-170 4-CH₃O A135 6-i-C₄H₉O 3-CH₃ CH₃ C₂H₅ 180-182 4-CH₃O A136 6-i-C₄H₉O 3-CH₃ H C₂H₅ 116-118 4-C₄H₉O A137 6-C₅H₁₁ H CH₃ CH₃ 138-140 A138 6-C₅H₁₁ H CH₃ C₂H₅ 94-96 A139 6-C₅H₁₁O H CH₃ CH₃ 115-117 A140 6-i-C₅H₁₁ H CH₃ CH₃ 138-139 A141 6-i-C₅H₁₁ H CH₃ C₂H₅ 101-103 A142 6-i-C₅H₁₁O H CH₃ CH₃ 112-113 A143 6-i-C₅H₁₁O H CH₃ C₂H₅ 128-130 A144 6-C₅H₁₃ H OH₃ CH₃ 123-125 A145 6-C₅H₁₃ H CH₃ C₂H₅ oil A146 6-C₅H₁₃O H CH₃ CH₃ 100-102 A147 6-C₅H₁₃O H CH₃ C₂H₅ 96-98 A148 6-i-C₅H₁₃O H CH₃ CH₃ 106-109 A149 6-C₈H₁₇ H CH₃ CH₃ 105-107 A150 6-C₈H₁₇ H CH₃ C₂H₅ oil A151 6-cyclohexyl H CH₃ CH₃ 221-222 A152 6-cyclohexyl H CH₃ C₂H₅ 154-156 A153 6-NO₂ H CH₃ CH₃ 279 (dec) A154 6-NH₂ H CH₃ CH₃ 227 A155 6-(CH₃)₂N H CH₃ CH₃ 179-183 A156 6-N-(2-dimethyl H CH₃ CH₃ methyl- aminoethylamino iodide 285 (dec) A157 6-i-C₄H₉NH H CH₃ CH₃ 183-186 A158 Compound No. 157 2HCl.½H₂O 194 (dec) A159 6-i-C₄H₉NH H CH₃ C₂H₅ H₂O 162 A160 6-i-C₄H₉NH H CH₃ C₂H₅ HCl 183 A161 6-pyrrolidino H CH₃ CH₃ 157-167 A162 6-pyrrolidino H CH₃ C₂H₅ 122-130 A163 6-piperazino H CH₃ CH₃ 186-196 A164 6-piperazino H CH₃ C₂H₅ 186-189 A165 6-(4-methyl H CH₃ C₂H₅ 111-113 piperazino) A166 6-(4-acetyl H CH₃ CH₃ 220-225 piperazino) A167 6-(4-acetyl H CH₃ C₂H₅ 200-204 piperazino) A168 6-morpholino H CH₃ CH₃ 241-243 A169 6-morpholino H CH₃ C₂H₅ 195-196 A170 6-C₆H₅ H CH₃ CH₃ 164-169 A171 6-C₆H₅ H CH₃ C₂H₅ 192-194 A172 6-(3-pyridyl) H H CH₃ oil A173 6-Cl H CH₃ CH₃ 187-189 A174 6-Cl H CH₃ C₂H₅ 160-161 A175 6-F H CH₃ CH₃ 192-193 A176 6-F H CH₃ C₂H₅ 193-196 A177 7-F H CH₃ CH₃ 219-221 A178 5-Cl H CH₃ CH₃ 207-208 6-i-C₄H₉O A179 5-Cl H CH₃ C₂H₅ 174-176 6-i-C₄H₉O A180 5-Cl 3-CH₃ CH₃ CH₃ 179-180 6-i-C₄H₉O A181 5-Cl 3-CH₃ CH₃ C₂H₅ 167-167 6-i-C₄H₉O A182 5-F H CH₃ CH₃ 172-173 6-i-C₄H₉O A183 5-F 4-O₂H₅ CH₃ CH₃ 205-207 6-i-C₄H₉O A184 5-CH₃ 3-CH₃ CH₃ C₂H₅ 165-167 6-CH₃O 4-CH₃ A185 5-CH₃ 3-CH₃ CH₃ C₂H₅ 175-176 6-i-C₃H₇O 4-i-C₃H₇O A186 5-CH₃ H H CH₃ 127 6-i-C₄H₉O A187 5-CH₃ H H C₂H₅ 182-184 6-i-C₄H₉O A188 5-CH₃ H CH₃ C₂H₅ 154-156 6-i-C₄H₉O A189 5-CH₃ 3-CH₃ H C₂H₅ 185-186 6-i-C₄H₉O 4-CH₃O A190 5-CH₃ 3-CH₃ CH₃ CH₃ 150-151 6-i-C₄H₉O 4-CH₃O A191 5-CH₃ 3-CH₃ CH₃ C₂H₅ 149 6-i-C₄H₉O 4-CH₃O A192 5-CH₃ 3-CH₃ CH₃ C₂H₅ 169-171 6-i-C₄H₉O 4-i-C₃H₇O A193 5-CH₃ 3-CH₃ H C₂H₅ 114-115 6-i-C₄H₉O 4-i-C₃H₇O A194 5-NH₂ H CH₃ CH₃ HCl 6-i-C₄H₉O 130-131 A195 5-i-C₃H₇ H CH₃ CH₃ 153-155 6-CH₃O A196 5-CH₃O H CH₃ CH₃ 130-131 6-i-C₄H₉O A197 5-i-C₄H₉O H CH₃ CH₃ oil 6-F A198 5-(N-methyl-N- H CH₃ CH₃ 120-122 (2-dimethyl- amino- ethyl)amino) 6-F A199 5,7-diF H CH₃ CH₃ 218-220 A200 5,7-diCH₃O H CH₃ CH₃ 220 A201 5-i-C₄H₉O H CH₃ CH₃ 120 7-F A202 6,7-diF H CH₃ CH₃ 194-197 A203 6-F H CH₃ CH₃ 216-219 7-i-C₄H₉O A204 6-F H CH₃ CH₃ 189-194 7-piperidino A205 6-F,7-(4-hydro- H CH₃ CH₃ >300  xypiperidino) A206 6-F H CH₃ CH₃ 221-225 7-pyrrolidino A207 6-F H CH₃ CH₃ 251-252 7-morpholino A208 6-F H CH₃ CH₃ 223-226 7-piperazino A209 6-F H CH₃ CH₃ 202-205 7-(4-methyl- piperazino) A210 6-F H CH₃ CH₃ 215-218 7-(4-acetyl- piperadino) A211 6-F,7-[N-methyl- H CH₃ CH₃ 189-190 N-(2-hydroxy- ethyl)amino A212 6-OH H CH₃ CH₃ >300  7-F A213 6-OH H CH₃ CH₃ >300  7-i-O₃H₇ A214 6-CH₃O H CH₃ CH₃ 210-213 7-F A215 6-C₂H₅O H CH₃ CH₃ 266-267 7-F A216 6-C₃H₇O H CH₃ CH₃ 198-200 7-F A217 6-C₄H₉O H CH₃ CH₃ 146-148 7-F A218 6,7-OCH₂O— H CH₃ CH₃ 185-189 A219 6,7- H CH₃ CH₃ 273-274 OC₂H₄N(CH₃)— A220 6,7-diCH₃O H CH₃ CH₃ 282-283 A221 6,7-diC₂H₅O H CH₃ CH₃ 219-221 A222 6,7-diC₃H₇O H CH₃ CH₃ 187-189 A223 6,7-di-i-C₄H₉O H CH₃ CH₃ 218-220 A224 6-CH₃O H CH₃ CH₃ 202-206 7-C₃H₅ A225 6-CH₃O H CH₃ CH₃ 175-177 7-C₃H₇ A226 6-CH₃O H CH₃ CH₃ 174-177 7-i-C₃H₇ A227 6-CH₃O H CH₃ C₂H₅ 133-134 7-i-C₃H₇ A228 6-CH₃O 4-C₂H₅ CH₃ CH₃ 172-175 7-i-C₃H₇ A229 6-CH₃O 4-i-C₃H₇ CH₃ CH₃ 182-183 7-i-C₃H₇ A230 6-CH₃O 3-CH₃ H CH₃ 197-199 7-i-C₃H₇ 4-CH₃O A231 6-CH₃O 3-CH₃ CH₃ CH₃ 200 7-i-C₃H₇ 4-CH₃O A232 6-CH₃O 3-CH₃ CH₃ C₂H₅ 170-171 7-i-C₃H₇ 4-CH₃O A233 6-i-C₄H₉O H H CH₃ 156-157 7-CH₃ A234 6-i-C₄H₉O H CH₃ CH₃ 202-204 7-CH₃ A235 6-i-C₄H₉O H CH₃ C₂H₅ 142-144 7-CH₃ A236 6-i-C₄H₉O 3-CH₃ H CH₃ 219-220 7-CH₃ 4-CH₃O A237 6-i-C₄H₉O 3-CH₃ CH₃ CH₃ 178-179 7-CH₃ 4-CH₃O A238 6-i-C₄H₉O 3-CH₃ CH₃ C₂H₅ 196 7-CH₃ 4-CH₃O A239 6-CH₃O H CH₃ CH₃ 239-242 7-CH₃H₅O A240 6-CH₃O H CH₃ CH₃ 215-222 7-C₃H₇O A241 6-CH₃O H CH₃ CH₃ 213-216 7-i-C₄H₉O A242 6-CH₃O H CH₃ CH₃ 210-213 7-CF₃ A243 6-CH₃O H CH₃ CH₃ 229-231 7-cyclohexyloxy A244 6-CH₃O H CH₃ CH₃ 216-218 7-C₆H₅O A245 6-CH₃O H CH₃ CH₃ >300  7-(4-pyridyl)oxy A246 6-CH₃O H CH₃ CH₃ 215-217 7-pyrrolidino A247 6-CH₃O H CH₃ CH₃ 230-237 7-piperidino A248 6-CH₃O H CH₃ CH₃ 246-248 7-morpholino A249 6-CH₃O H CH₃ CH₃ 234-236 7-thiomorpholino A250 6-CH₃O H CH₃ CH₃ 217-220 7-piperazino A251 6-CH₃O H CH₃ CH₃ 231-233 7-(4-methyl- piperazino) A252 6-CH₃O H CH₃ CH₃ 247-249 7-(4-acetyl- piperazino) A253 6-CH₃O H CH₃ CH₃ 252-254 7-pyrrolyl A254 6-CH₃O H CH₃ CH₃ 180-182 7-(1-pyrazolyl) A255 6-CH₃O H CH₃ CH₃ 254-257 7-(1-imidazolyl) A256 6-CH₃O H CH₃ CH₃ 241-245 7-(1-triazolyl) A257 6-C₂H₅O H CH₃ CH₃ 128-130 7-i-C₃H₇ A258 6-i-C₃H₇O H CH₃ CH₃ 126-128 7-i-C₃H₇ A259 6-i-C₃H₇O H CH₃ CH₃ 126-128 7-i-C₃H₇ A260 6-i-C₄H₉O H CH₃ CH₃ 241-242 7-CH₃O A261 6-i-C₄H₉O H CH₃ CH₃ 134-137 7-i-C₃H₇ A262 6-i-C₄H₉O H CH₃ CH₃ 176-177 7-CF₃ A263 6-i-C₄H₉O H CH₃ CH₃ 198-203 7-pyrrolidino A264 6-i-C₄H₉O H CH₃ CH₃ 224-225 7-piperidino A265 6-i-C₄H₉O H CH₃ CH₃ 216-219 7-morpholino A266 6-acetoxy H CH₃ CH₃ 139 7-CH₃ A267 6-hydroxy- H CH₃ CH₃ >300  carbonyloxy 7-CH₃ A268 6-ethoxy- H CH₃ CH₃ 169-170 carbonyloxy 7-CH₃ A269 6-hydroxy- H CH₃ CH₃ >300  carbonylmethoxy 7-CH₃ A270 6-i-C₃H₇ H CH₃ C₂H₅ 232 7-CH₃O A271 6-ethoxy- H CH₃ CH₃ 183-184 carbonyloxy 7-i-C₃H₇ A272 7,8-diF H CH₃ CH₃ 226-228 A273 7-i-C₃H₇ H CH₃ CH₃ 144-145 8-CH₃O A274 7-i-C₃H₇ 4-C₂H₅ CH₃ CH₃ 152-155 8-CH₃O A275 7-i-C₄H₉ H CH₃ CH₃ oil 8-F A276 5,7-diCl H CH₃ CH₃ 223-226 8-CH₃O A277 5,7-diCl H CH₃ C₂H₅ 180-182 6-CH₃O A278 5,7-diCl H CH₃ CH₃ 196-199 6-i-C₄H₉O A279 5,7-diCl H CH₃ C₂H₅ 193-194 6-i-C₄H₉O A280 5-Cl H CH₃ CH₃ 184-186 6-CH₃O 7-i-C₃H₇ A281 5-Cl H CH₃ C₂H₅ 154-155 6-CH₃O 7-i-C₃H₇ A282 5-Cl H CH₃ CH₃ 188-189 6- i-C₄H₉O 7-CH₃ A283 5-Cl H CH₃ C₂H₅ 205-207 6-i-C₄H₉O 7-CH₃ A284 5-Cl H CH₃ C₂H₅ 183-186 6-i-C₄H₉O 7-Cl A285 5,7-diCH₃ H H CH₃ 170-172 6-i-C₄H₉O H A286 5,7-diCH₃ H CH₃ CH₃ 158-160 6-i-C₄H₉O A287 5,7-diCH₃ H CH₃ C₂H₅ 175-178 6-i-C₄H₉O A288 5,7-diCH₃ 3-CH₃ CH₃ CH₃ 155-157 6-i-C₄H₉O 4-CH₃O A289 5,7-diCH₃ 3-CH₃ CH₃ C₂H₅ 154-157 6-i-C₄H₉O 4-CH₃O

TABLE II Com- pound m.p. No. R₁ R₂′ R₃′ R₄ (° C.) A290 6-C₃H₇ CH₃ C₆H₅ CH₃ 241-245 A291 6-i-C₃H₇ CH₃ CH₃ CH₃ 188-189 A292 6-i-C₃H₇ CH₃ C₄H₉ CH₃ 106-107 A293 6-i-C₃H₇ CH₃ C₄H₉ C₂H₅ oil A294 6-i-C₃H₇ C₃H₇ H CH₃ 132-134 A295 6-i-C₃H₇ 2-pyridyl H CH₃ 124-126 A296 6-i-C₃H₇ 2-pyridyl H C₂H₅ 144-146 A297 6-i-C₃H₇ 3-pyridyl H CH₃ 164-166 A298 6-i-C₃H₇ 3-pyridyl H C₂H₅ 148-149 A299 6-i-C₃H₇ 3-pyridyl CH₃ CH₃ 242-243 A300 6-i-C₃H₇ 4-pyridyl H CH₃ 192-193 A301 6-i-C₃H₇ 4-pyridyl H C₂H₅ 229-230 A302 6-i-C₃H₇ 2-pyradinyl H C₂H₅  94-96 A303 6-i-C₃H₇ 2-furyl H CH₃  86-88 A304 6-i-C₃H₇ 2-furyl H C₂H₅  70-73 A305 6-i-C₃H₇ N—CH₃- H C₂H₅ 101-104 2-pyrrolyl A306 6-i-C₃H₇ N—CH₃- H CH₃ 173-176 3-pyrrolyl A307 6-i-C₃H₇ N—CH₃- H C₂H₅ 132-134 3-pyrrolyl A308 6-i-C₃H₇ 2-thienyl H CH₃ 111-113 A309 6-i-C₃H₇ 2-thienyl H C₂H₅  95-96 A310 6-i-C₃H₇ 2-thienyl CH₃ CH₃ 136-137 A311 6-i-C₃H₇ 2-thienyl CH₃ C₂H₅ 169-173 A312 6-i-C₃H₇ 3-thienyl H CH₃ 164-166 A313 6-i-C₃H₇ 3-thienyl H C₂H₅ 118-120 A314 6-i-C₃H₇ 5-CH₃- H CH₃ 132 2-thienyl A315 6-i-C₃H₇ 5-CH₃- H C₂H₅ 121-122 2-thienyl A316 6-i-C₃H₇ 5-Br-2-thienyl H CH₃ 183-185 A317 6-i-C₃H₇ 5-Br-2-thienyl H C₂H₅ oil A318 5-CH₃ 2-thiernyl CH₃ CH₃ 111-112 6-i-C₄H₉O A319 6-i-C₃H₇ 2-thiazolyl H C₂H₅  91-93 A320 6-i-C₃H₇ C₆H₅ CH₃ C₆H₅ 225 A321 6-i-C₃H₇ C₆H₅ CH₃ 2-F—C₆H₄ 205-207 A322 6-i-C₃H₇ C₆H₅ CH₃ 3-F—C₆H₄ 248-251 A323 6-i-C₃H₇ C₆H₅ CH₃ 4-F—C₆H₄ 224-229 A324 6-i-C₃H₇ C₆H₅ CH₃ 4-Cl—C₆H₄ 233-235 A325 6-i-C₃H₇ C₆H₅ CH₃ 4-CH₃—C₆H₄ 203-205 A326 6-i-C₃H₇ C₆H₅ CH₃ 4-CH₃O— 204-208 C₆H₄ Part B.

Example 7 5-Ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one(Compound B2)

To a 1.6M solution of n-butyl lithium in hexane (6.6 mL, 10.5 mmol) was added tetramethylethylenediamine (1.58 mL, 10.5 mmol) under argon atomosphere at room temperature with stirring. To this was added with ice cooling a solution of 1-indanone (1.38 g, 10.5 mmol) in anhydrous THF followed by stirring at room temperature for 1 hour. After ice cooling the mixture, a solution of 1-ethyl-6-isopropylisatoic anhydride prepared in step 1 of Example 6 (1.22 g, 5.2 mmol) in anhydrous THF was added dropwise thereto. The mixture was stirred at room temperature overnight and then duluted with saturated aqueous solution of ammonium chloride. The organic layer was separated and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution and dried with sodium sulfate followed by evaporating to remove the solvent. The residue was purified by silica gel-chromatography (chloroform) and crystallization from diethyl ether to obtain the desired compound. ¹H-NMR (CDCl₃) δ 1.32 (6H, d, CH(CH ³ )₂), 1.70 (3H, t, CH₂ CH ³ ), 3.09 (1H, septet, CH), 3.91 (2H, s, H-11), 4.71 (2H, q, NCH₂), 7.47-7.94 (6H, m, Ar—H), 8.44 (1H, s, H-9)

Example 8 2.5-Diethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound B9)

Step 1. 3-Chloro-1-(4-ethylphenyl)-1-propanone

To a solution of anhydrous aluminum chloride (20 g, 0.15 mmol) in nitrobenzene(50 mL) was added dropwise a solution (30 mL) of ethylbenzene(13.5 mL, 0.11 mmol) and 3-chloropropionyl chloride (25 g, 0.20 mmol) in nitrobenzene. The mixture was stirred at room temperature for 3 hours and then poured into ice-water (600 mL) containing 100 mL of concentrated hydrochloric acid followed by extraction with diethyl ether. The combined organic layers were washed with water and saturated sodium chloride solution, dried with sodium sulfate and evoparated to remove diethyl ether and nitrobenzene under reduced pressure. The residue was crystallized from n-hexane to give the title compound (9.1 g, 42.1%). ¹H-NMR (CDCl₃) δ 1.26 (3H, t, CH₂ CH ³ ), 2.72 (2H, q, CH ² CH₃), 3.44 (2H,t,COCH₂), 3.93 (2H, t, CH₂Cl), 7.31 (2H, d, Ar—H), 7.89 (2H, d, Ar—H)

Step 2. 5-Ethyl-1-indanone

3-Chloro-1-(4-ethylphenyl)-1-propanone (9.1 g, 46.3 mmol) was dissolved in 50 mL of conc. H₂SO₄ and heated at 100° C. for 30 minutes with stirring. The reaction mixture was poured onto crashed ice (500 g). The resulting precipitate was filtered off, washed with water and then dissolved in diethyl ether. The solution was washed with water and saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness. The title compound was obtained by crystallizing the residue from n-hexane. ¹H-NMR (CDCl₃) δ 1.28 (3H, t, CH₂ CH ³ ), 2.67-2.70 (2H, m,H-3), 2.74 (2H, q, CH ² CH₃), 3.11 (2H, dd, H-2), 7.21 (1H, d, Ar—H), 7.30 (1H, s, H-4), 7.68 (1H, d, Ar—H)

Step 3. 2,5-Diethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one

To a 1.53M solution of n-butyl lithium in hexane (13.2 mL, 20.2 mmol) was added TMEDA (3.1 mL, 20.2 mmol) under argon atmosphere at room temperature with stirring. To this was added with ice cooling a solution of 5-ethyl-1-indanone(3.24 g,20.2 mmol) in anhydrous THF followed by stirring at room temperature for 1 hour. After ice cooling the mixture, a solution of 1-ethyl-6-isopropylisatoic anhydride (Example 6, step 1) (2.35 g, 10.1 mmol) in anhydrous THF was added dropwise thereto. The mixture was stirred at room temperature overnight and diluted with saturated aqueous solution of ammonium chloride. The orgaic layer was separated and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution and dried with sodium sulfate. After removing the solvent, the residue was purified by silica gel-chromatography (chloroform:acetone=20:1) and crystallization from diethyl ether to give the desired compound. ¹H-NMR (CDCl₃) δ 1.32 (3H, t, CH₂ CH ³ ), 1.34 (6H, d, CH(CH ³ )₂), 1.70 (3H, t, NCH₂ CH ³ ), 2.78 (2H, q, CH ² CH₃), 3.10 (1H, septet, CH), 3.91 (2H, s, H-11), 4.72 (2H, q, NCH₂), 7.30-7.85 (5H, m, Ar—H), 8.45 (1H, s, H-9)

Example 9 2-Ethyl-9-isopropyl-6,12-dihydrobenzo[c]acridin-7 (5H)-one (Compund B25)

To a 1.6M solution of n-butyl lithium in hexane (1.6 mL, 2.6 mmol) was added TMEDA (0.4 mL, 2.6 mmol) under argon atmosphere at room temperature with stirring. To this was added with ice cooling a solution of 1-tetralone (0.38 g, 2.6 mmol) in anhydrous THF followed by stirring for 1 hour under ice cooling. Thereafter, a solution of 1-ethyl-6-i-propylisatoic anhydride (0.3 g, 1.3 mmol) in anhydrous THF was added dropwise followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with saturated aqueous solution of ammonium chloride. The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution and dried with sodium sulfate. After removing the solvent, the residue was purified by silica gel-chromatography (chloroform) followed by crystallization from petroleum ether to give the desired compound. ¹H-NMR (CDCl₃) δ 1.15 (3H, t, NCH₂ CH ³ ), 1.33 (6H, d, CH(CH ³ )₂), 2.79-2.86 (4H, m, CH₂CH₂), 3.07 (1H, septet, CH), 4.62 (2H, q, NCH₂), 7.32-7.60 (6H, m, Ar—H), 8.33 (1H, d, H-8)

The following compounds have been synthesized in a manner analogous to Examples 7-9.

The numbering of various substituents are those of respective fused ring systems, namely indeno[1,2-b]quinoline(x=1),benzo[c]acridine(x=2) and benzo[6,7]cyclohepta[1,2-b]quinoline, respectively.

TABLE III Com- pound No. x R₄ R₅ R₁ B1 1 CH₃ H 8-i-C₃H₇ 249 (dec) B2 1 C₂H₅ H 8-i-C₃H₇ 152-155 B3 1 Compound 175-177 B2, HCl salt B4 1 C₂H₅ H 8-CH₃O 205-207 B5 1 C₂H₅ H 6-F 241-243 B6 1 CH₃ H 8-CH₃O 297 9-i-C₃H₇ (dec) B7 1 C₂H₅ H 8-CH₃O 217-218 9-i-C₃H₇ B8 1 CH₃ 2-C₂H₅ 8-i-C₃H₇ 220 (dec) B9 1 C₂H₅ 2-C₂H₅ 8-i-C₃H₇ 205 B10 1 C₂H₅ 2-CH₃O 8-i-C₃H₇ 202-204 B11 1 CH₃ 2-CH₃O 8-i-C₄H₉ 218 B12 1 C₂H₅ 2-CH₃O 8-i-C₄H₉ 216-217 B13 1 CH₃ 2-CH₃O 8-i-C₃H₇ 215-222 B15 1 C₂H₅ 2-CH₃O 8-i-C₄H₉ 189-190 B16 1 CH₃ 2-Cl 8-i-C₃H₇ 265 (dec) B17 1 C₂H₅ 2-Cl 8-i-C₃H₇ 186 (dec) B18 1 CH₃ 2-Br 8-i-C₃H₇ 280 (dec) B19 1 C₂H₅ 2-Br 8-i-C₃H₇ 225 (dec) B20 1 C₂H₅ 2-OCH₃ 8-i-C₃H₇ 217 3-CH₃ (dec) B21 1 CH₃ 2,3-diCH₃O 8-i-C₃H₇ 253-254 B22 1 C₂H₅ 2,3-diCH₃O 8-i-C₃H₇ 208 B23 1 C₂H₅ 1,2-diCl 8-i-C₃H₇ 235 (dec) B24 2 CH₃ H 9-i-C₃H₇ 199-203 B25 2 C₂H₅ H 9-i-C₃H₇ oil B26 2 CH₃ H 9-i-C₄H₉O 160 B27 2 C₂H₅ H 9-i-C₄H₉O  61 B28 3 CH₃ H 10-i-C₃H₇ 167 B29 1 4-FC₆H₄ 2-CH₃O 8-i-C₃H₇ 285 (dec) B30 1 4-FC₆H₄ 2-C₂H₅ 8-i-C₃H₇ 270 (dec) B31 1 C₆H₄ 2-CH₃O 8-i-C₃H₇ 208-210 B32 1 C₂H₅ 2-CH₃O 7-i-C₃H₇ 224-225 8-CH₃O B33 1 C₂H₅ 2-C₂H₅ 7-i-C₃H₇ 210-212 8-CH₃O B34 1 C₂H₅ H 7,9-diCH₃ 184 8-i-C₄H₉ B35 1 C₂H₅ 2-CH₃O 7,9-diCH₃ 203-204 8-i-C₄H₉ B36 1 C₂H₅ 2-C₂H₅ 7,9-diCH₃ 140 8-i-C₄H₉ B37 1 C₂H₅ 1,3-diCH₃ 8-i-C₃H₇ 201 2-CH₃O B38 1 4-FC₆H4 2-C₂H₅ 7-i-C₃H₇ 281 8-CH₃O (dec) B39 1 C₂H₅ H 8-i-C₄H₉O 239-240 9-CH₃ Part C.

Example 10 5-Ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (Compound C47)

Under argon atmosphere, 60% sodium hydride (82 mg, 2.0 mmol) was added to a solution of 1,3-indandione (300 mg,2.0 mmol) in anhydrous DMF with ice cooling and stirring followed by stirring for additional 1 hour. To the mixture was added dropwise a solution of 1-ethyl-6-isopropylisatoic anhydride (238 mg,1.0 mmol) in anhydrous DMF followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into ice-water. The resulting precipitate was filtered off, washed with water and dissolved in chloroform. The chloroform solution was washed with saturated sodium chloride solution and dried with sodium sulfate followed by evaporation to remove chloroform. The title compound was obtained by crystallizing from diethyl ether. ¹H-NMR (CDCl₃) δ 1.30 (6H, d, CH(CH ³ )₂, 1.73 (3H, t, NCH₂ CH ³ ), 3.03 (1H, septet, CH), 4.69 (2H, q, NCH₂), 7.46-7.71 (6H, m, Ar—H), 8.33 (1H, s, H-9)

Example 11 5-Ethyl-8-isopropyl-11-hydroxyimino-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C48)

5-Ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (300 mg, 0.95 mmol) was dissolved in a solution of hydroxylamine hydrochloride (525 mg, 7.6 mmol) and triethylamine (0.5 mL) in 20 mL of ethanol. The solution was refluxed overnight and then concentrated dryness. The residue was diluted with water and extracted with chloroform twice. The combined organic layers were washed with saturated sodium chloride solution, dried with sodium sulfate followed by evaporation to remove the solvent. The title compound was obtained by subjecting the resulting residue to silica gel-chromatography (chloroform:actone=20:1) and then to crystallization from diethyl ether. ¹H-NMR (CDCl₃) δ 1.32 (6H, d, CH(CH ³ )₂, 1.73 (3H, t, NCH₂ CH ³ ), 3.03 (1H, septet, CH), 4.79 (2H, q, NCH₂), 7.41-8.00 (6H, m, Ar—H), 8.25 (1H, s, H-9), 15.31 (1H, s, N═OH)

Example 12 5-Ethyl-8-isopropyl-11-hydroxy-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C43)

To an ethanolic solution of 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (500 mg, 1,58 mmol) was added sodium borohydride (62 mg, 1.64 mmol) in portions followed by stirring at room temperature for 1 hour. After removing ethanol, the reaction mixture was diluted with water and extracted with chloroform twice. The combined organic layers were washed with saturated sodium chloride solution and dried with sodium sulfate followed by evaporating to remove chloroform. The title compound was obtained by crystallizing the residue from acetone-diethyl ether mixture. ¹H-NMR (CDCl₃) δ 1.35 (6H, d, CH(CH ³ )₂), 1.72 (3H, t, NCH₂ CH ³ ), 3.11 (1H, septet, CH), 4.79 (2H, q, NCH₂), 5.86 (1H, s, H-11), 7.52-7.63 (3H, m, Ar—H), 7.85 (1H, dd, H-9)

Example 13 5-Ethyl-8-isopropyl-11-hydroxy-11-phenyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C45)

2M solution of phenyl magnesium bromide in THF (1.07 mL, 1.87 mmol) was dissolved in anhydrous methylene chloride. To this solution was added dropwise a solution of 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (500 mg, 1.58 mmol) in anhydrous methylene chloride with ice cooling and stirring followed by stirring at room temperature overnight. The reaction mixture was treated with 10% hydrochloric acid. The organic layer was separated, washed sequentially with diluted hydrochloric acid and saturated sodium chloride solution and dried with sodium sulfate followed by evaporation to remove methylene chloride. The title compound was isolated by subjecting the residue to silica gel-chromatography (chloroform) and crystallization from diethyl ether. ¹H-NMR (CDCl₃) δ 1.30 (6H, d, CH(CH ³ )₂), 1,79 (3H, t, NCH₂ CH ³ ), 3.05 (1H, septet, CH), 4.81 (2H, q, NCH₂), 5.18 (1H, s, H-11), 7.16-7.64 (10H, m, Ar—H), 7.96 (1H, d, H-6), 8.37 (1H, d, H-9)

Example 14 5-Ethyl-8-isopropyl-11-phenyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C44)

To a mixture of trimethylsilyl chloride (0.19 mL, 1.5 mmol), sodium iodide (224 mg, 1.5 mmol) and acetonitrile (61 mg, 1.5 mmol) was added dropwise a solution of 5-ethyl-8-isopropyl-11-hydroxy-11-phenyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one in 1,2-dichloroethane with stirring at room temperature. The mixture was stirred at 50° C. overnight followed by allowing to cool to room temperature. The reaction mixture was treated diluted aqueous solution of sodium sulfite. The separated organic layer was washed with water four times and then with saturated sodium chloride solution followed by drying with sodium sulfate. After removing the solvent, the residue was purified by silica gel-chromatography (chloroform) followed by crystallization from diethyl ether to give the title compound. ¹H-NMR (CDCl₃) δ 1.30 (6H, d, CH(CH ³ )₂), 1.79 (3H, t, NCH₂ CH ³ ), 3.05 (1H, septet, CH), 4.81 (2H, q, NCH₂), 5.18 (1H, s, H-11), 7.16-7.64 (10H, m, Ar—H), 7.96 (1H, d, H-6), 8.37 (1H, d, H-9)

Example 14 5-Ethyl-8-methoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (Compound C60)

Step 1. 3-Methyl-4-methoxynitrobenzene

A solution of 2-fluoro-5-nitrotoluene (7.0 g, 45 mmol) in anhydrous DMF was added to a 28% methanolic solution of sodium methoxide (10.45 g, 54 mmol) under ice-cooling with stirring. The reaction mixture was stirred at room temperature overnight and then poured into ice water. The resulting precipitate was filtered off and dissolved in diethyl ether. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness to give the desired compound. ¹H-NMR (CDCl₃) δ 2,27 (3H, s, CH₃), 3.94 (3H, s, OCH₃), 6.87 (1H, d, H-5), 8.03 (1H, d, H-2), 8.11 (1H, dd, H-6)

Step 2. 2-Bromo-4-methoxy-5-methylaniline

To a solution of 3-methyl-4-methoxynitrobenzene(7.59 g, 45 mmol) in ethanol was added-iron powder (35 g), water(5 mL) and concentrated hydrochloric acid (0.4 mL). The mixture was refluxed for 1 hour and then filtered while hot. The filtrate was concentrated to dryness. The residue was dissolved in chloroform. The chloroform solution was dried with sodium sulfated and evaporated to give 3-methyl-4-methoxyaniline (7.59 g). To a solution of this compound (6.17 g, 45 mmol) in acetic acid (55 mL) were added dropwise acetic anhydride (4,4 mL, 46 mmol) at room temperature with stirring and then bromine(2,4 mL, 46 mmol) at 50° C. with stirring. The reaction mixture was stirred at the same temperature for 2 hours and poured into ice-water. The resulting precipitate was filtered off, washed with water and dissolved in ethyl acetate. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness to give 2-bromo-4-methoxy-5-methylacetanilide as a crude product. Crystallization from diethyl ether gave pure product (8.27 g).

This product was dissolved in ethanol and concentrated hydrochoric acid (26 mL) was added thereto. The mixture was refluxed for 2 hours and then concentrated to dryness. The residue was made weak alkaline with sodium hydroxide. The resulting precipitate was filtered off, washed with water and dried under reduced pressure to give the desired compound. ¹H-NMR (CDCl₃) δ 2.11 (3H, s, CH₃), 3,74 (3H, s, OCH₃), 3.74 (2H, m, NH₂), 6.61 (1H, d, Ar—H), 6.87 (1H, s, Ar—H)

Step 3. 5-Methyl-6-methoxy-8-bromoisatoic Anhydride

The title compound was prepared from 2-bromo-4-methoxy-5-methylaniline via 4-methyl-5-methoxy-7-bromoisatin in a manner analogous to that described in Example 5.

Step 4. 1-Ethyl-5-methyl-6-methoxyisatoic Anhydride

5-methyl-6-methoxy-8-bromoisatoic anhydride (1,39 g, 4.8 mmol) in DMF was hydrogenated in the presence of 5% Pd—C overnight. After filtering, the reaction mixture was concentrated to dryness and dissolved in ethyl acetate. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness to give 5-methyl-6-methoxyisatoic anhydride. Reaction of this compound with ethyl iodide in the presence of sodium hydride gave the title compound.

Step 5. 5-Ethyl-8-methoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione

1-Ethyl-5-methyl-6-methoxyisatoic anhydride was reacted with 1,3-indandione as in Example 10 to give the desired compound. ¹H-NMR (CDCl₃) δ 1.70 (3H, t, NCH₂ CH ³ ), 2.83 (3H, s, CH₃), 3.88 (3H, s, OCH₃), 4.64 (2H, q, NCH₂), 7.18-7.69 (6H, m, Ar—H)

Example 15 5-Ethyl-8-isobutoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (Compound C61)

To a solution of boron tribromide (0.3 mL, 3,3 mmol) in methylene chloride was added dropwise a solution of 5-ethyl-8-methoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione(325 mg, 1.0 mmol) in methylene chloride under ice cooling with stirring followed by stirring at room temperature overnight. The reaction mixture was poured into a 10% aqueous solution of sodium hydroxide. The aqueous layer was acidified with hydrochloric acid to yield a precipitate. This precipitate was filtered off, washed with water and dried under reduced pressure to give the corresponding 8-hydroxy compound (331 mmg, 100%). This product (331 mg, 1.0 mmol) was dissolved in anhydrous DMF and 60% sodium hydride (48 mg, 1.2 mmol) was added thereto at room teperature with stirring.After stirring for 1 hour, the reaction mixture was allowed to react with isobutyl bromide (0.1 mL, 1.5 mmol) added thereto at 60° C. overnight with stirring. The reaction mixture was concentrated to dryness and the residue was dissolved in chloroform. The chloroform solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness. The residue was purifie by silida gel-chromatography (chloroform:methanol=30:1) to obtain the desired compound. ¹H-NMR (CDCl₃) δ 1.08 (6H, d, OCH₂CH(CH ³ )₂), 1.67 (3H, t, NCH₂ CH ³ ), 2.13 (1H, m,OCH₂ CH(CH₃)₂), 2.80 (3H, s, CH₃), 3.72 (2H, d, OCH ² CH(CH₃)₂), 4.64 (2H, q, NCH₂), 7.10-7.63 (6H, m, Ar—H)

Example 16 5-Ethyl-8-isobutoxy-9-methyl-11-hydroxy-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C62)

5-Ethyl-8-isobutoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione was treated as in Example 12 to give the title compound. ¹H-NMR (CDCl₃) δ 1.10 (6H, d, OCH₂CH(CH ³ )₂), 1.69 (3H, t, NCH₂ CH ³ ), 2.17 (1H, m,OCH₂ CH(CH₃)₂), 3.00 (3H, s, CH₃), 3,81 (2H, d, OCH ² CH(CH₃)₂), 4.31 (1H, s, H-11), 4.65 (2H, q, NCH₂), 5,80 (1H, s, OH), 7.28-7.74 (6H, m, Ar—H)

Starting from 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (Compound C47), the following compound have been prepared using known methodology.

5-Ethyl-8-isopropyl-11-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C40) mp 152-154;

5-Ethyl-8-isopropyl-11-amino-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one dihydrochloride (Compound C41), mp 200° C. (decomp);

5-Ethyl-8-isoproypl-11-methoxyimino-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C49) mp 150° C.

5-Ethyl-8-isopropyl-11-acetylamino-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C42), mp215° C. (decomp); and

5-Ethyl-8-isopropyl-11-methoxy-11-phenyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one, (Compound C46), mp 237-239.

Example 17 10-Ethyl-7-isopropyl-2-methyl-5,10-dihydro-4H-thieno[3′,2′:4,5]cyclopenta[1,2-b]quinolin-5-one (Compound D51)

Step 1. 3-Chloro-1-(5-methyl-2-thienyl)-1-propanone

To a suspension of anhydrous aluminum chloride (4 g,0.03 mol) in nitrobenzene (10 mL) was added dropwise a solution of 2-methylthiophene (2.0 g, 0.02 mol) and 3-chloropropionyl chloride (3.8 g, 0.20 mol) in nitrobenzene (10 mL). After stirring for 3 hours, the reaction mixture was poured into ice-water (200 mL) containing concentrated hydrochloric acid (20 mL) followed by extraction with diethyl ether. The orgaic layer was sequentially washed with water and saturated sodium chloride solution dried with sodium sulfate and evaporated to remove diethyl ether. The residue was further evaporated under reduced pressure to remove nitrobenzene and purified by silica gel-chromatography (hexane:ethyl acetate=19:1) to give the desired compound (2.5 g, 66.2%). ¹H-NMR (CDCl₃) δ 2.54 (3H, s, CH₃), 3.32 (2H, t, CH₂Cl), 3,89 (2H,t,COCH₂), 6.81-6.83 (1H, m,H-4), 7.56 (1H, d, H-3)

Step 2. 2-Methyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one

3-Chloro-1-(5-methyl-2-thienyl)-1-propanone (2,5 g,13.2 mmol) was heated in concentrated sulfuric acid (20 mL) at 100° C. for 50 minutes with stirring. The reaction mixture was gradually poured into ice-water (200 g) and extracted with diethyl ether. The organic layer was sequnetially washed with water and saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness. The residue was purified by silica gel-chromatography (chloroform) to give the desired compound.

¹H-NMR (CDCl₃) δ 2.57 (3H, s, CH₃), 2.87-2.97 (4H, m,COCH₂CH₂), 6.75 (1H, s, H-3)

Step 3. 10-Ethyl-7-isopropyl-2-methyl-5,10-dihydro-4H-thieno[3′,2′:4,5]cyclopenta[1,2-b]quinolin-5-one

To a 1.53M solution of n-butyl lithium in hexane (0.47 mL, 0.72 mmol) were added under argon atmosphere TMEDA (0.11 mL, 0.72 mmol) at room temperature and then 2-methyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (0.11 g, 0.72 mmol) in anhydrous THF dropwise with ice cooling and stirring. The reaction mixture was stirred at room temperature for 1 hour and ice-cooled again. To this was added dropwise a solution of 1-ethyl-6-isopropylisatoic anhydride (Example 6, step 1) (0.11 g, 0.48 mmol) in anhydrous THF. The reaction mixture was stirred at room temperature for 2 hours and diluted with saturated aqueous solution of ammonium chloride. The organic layer was concentrated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated again. The residue was subjected to silica gel-chromatography (chloroform: acetone=9:1) and crystallization from diethyl ether to give the title compound. ¹H-NMR (CDCl₃) δ 1.33 (6H, d, CH(CH ³ )₂), 1.58 (3H, t, CH₂ CH ³ ), 2.64 (3H, s, CH₃), 3.10 (1H, septet, CH), 3,78 (2H, s, H-4), 4,49 (2H, q, NCH₂), 6.97 (1H, s, H-3), 7.49 (1H, d, H-9), 7.56 (1H, dd, H-8), 8.45 (1H, d, H-6)

The following compounds have been synthesized in a manner analogous to that described in Example 17.

10-Ethyl-7-isopropyl-5,10-dihydro-4H-thieno[3′,2′:4,5]cyclopenta[1,2-b]quinolin-5-one (Compound D50), mp 168-169° C.

10-Ethyl-7-isopropyl-3-methyl-5,10-dihydro-4H-thieno[3′,2′:4,5]cyclopenta[1,2-b]quinolin-5-one (compound D52), mp 195° C. (decomp); and

4-Ethyl-7-isopropyl-1-methyl-4,9-dihydro-10H-pyrrolo[2′,3′:4,5]cyclopenta[1,2-b]quinolin-9-one (Compound D53), mp 91-93° C.

BIOLOGICAL EXAMPLES

1. In Vitro Anti-Picornavirus Activity

Poliovirus type 1 (Polio 1, Sabin), echovirus type 11 (Echo 11, Gregory), coxsackievirus type A7 (CA7), coxsackievirus type B4 (CB4,JVB), human rhinovirus type 1B (HRV 1B, B632), HRV 2 (HGP), and HRV 89 (41617-Gallo) were used. Polio 1, Echo 11, and CA7 were assayed in HeLa-S3 cells with the exception of the CB4, which were assayed in HeLa cells; all numbered HRV serotypes were assayed in HeLa (Ohio strain)cells. Cells were seeded at 2.0×10⁴ cells/well (in Eagle MEM plus 7% fetal bovine serum, growth medium) in 96-well tissue culture plate and were incubated for 24 hr. at 37° C. in a CO₂ incubator to form monolayer. The growth medium in the plates was removed and a serial 0.5 log₁₀ dilutions of the test compound in 50 μl maintenance medium (Eagle MEM plus 2% heat-inactivated fetal bovine serum) was added to the wells. Each drug concentration was run in quadruplicate. Immediately after addition of compounds, the cells in 96-well plate were infected with appropriate virus at 300-1,000 plaque forming units (PFU) per well in 50 μl of maintenance medium and were incubated at 33° C. for HRVs or 37° C. for enteroviruses. Uninfected cells and cells that received virus in the absence of compound were included on each plate. The anti-picornavirus activities of the compounds were examined by calorimetric assay based on the cells as monitored by reduction of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) to formazan. After 3-5 days, 20 μl of MTT solution (4 mg/ml) in phosphate buffered saline (PBS) was added to each well, and the incubation was continued for an additional 2.5-4 hr. After incubation, 100 μl of 15% SDS in 0.01 N HCl was added to each well to solubilize the bluish violet crystal of formazan and the plates were incubated at 37° C. for an additional 18 hr. The absorbency of formazan at 600 nm with a reference wave length of 660 nm was measured by a computer-controlled microplate reader. The 50% inhibitory concentration (IC₅₀) by the MTT method was defined as the concentration of compound that protected 50% of the cell monolayer from virus-induced cytopathic effect. The percentage protection was calculated by the following equation: [(A_(T))v−(Ac) v/(Ac)_(mock)−(Ac)v]×100%, where (A_(T))v, (Ac)v, (Ac)_(mock) indicate absorbencies of the test sample, the virus-infected control (no compound) and mock-infected control, respectively.

The cytotoxicity of the compound was determined as described above without inoculation of the virus and expressed as the 50% cytotoxic concentration (CC₅₀), i.e., the concentration required to reduce the viability of untreated cells by 50%. The cells were exposed to various concentrations of the test compounds in the maintenance medium and incubated for 4 days.

A majority of the compounds of the present invention exhibited anti-picornavirus activities as shown in table IV-VI.

TABLE IV in vitro Anti-picornavirus activity IC₅₀(μg/ml) Com- pound Polio 1 Echo 11 CA7 CB4 HRV1B HRV2 HRV89 A30 1.0 0.42 1.2 1.8 1.6 0.48 1.0 A32 0.93 0.40 1.9 >3.3 1.0 0.55 0.77 A37 1.1 0.91 3.8 6.7 1.0 0.83 0.54 A60 1.1 0.52 2.5 2.8 0.59 0.52 1.1 A61 0.73 0.40 >4 >4 0.64 0.65 0.38 A78 1.3 1.2 7.1 2.6 5.6 1.7 2.9 A81 0.78 0.52 0.78 2.2 1.7 0.86 0.55 A97 0.54 0.3 2.1 1.4 0.58 0.61 0.14 A98 0.66 0.26 2.9 1.2 0.78 0.42 0.36 A99 0.55 0.20 1.8 1.1 0.63 0.50 0.14 A100 0.57 0.24 4.5 1.4 0.85 0.43 0.20 A122 1.2 0.54 6.9 5.5 0.59 0.43 0.35 A130 0.86 0.32 0.17 >4 0.90 0.65 0.72 A157 0.59 0.27 3.8 4.9 1.0 0.56 1.3 A159 0.51 0.26 2.7 3.0 0.78 0.48 0.73 A160 0.55 0.27 2.7 2.9 0.73 0.45 0.78 A169 4.3 1.1 >50 18 8.2 1.0 5.4 A171 0.52 0.22 1.9 2.0 0.43 0.76 0.39 A179 0.29 0.20 2.4 1.2 0.86 0.87 0.37 A181 0.39 0.24 2.4 1.8 1.6 0.94 0.46 A186 0.67 0.27 3.0 1.2 1.1 >1.7 0.26 A187 0.53 0.21 3.0 0.99 0.71 0.57 0.15 A188 0.31 0.27 1.2 1.1 0.81 0.33 0.25 A190 0.58 0.23 3.2 2.4 2.0 0.57 0.28 A191 0.40 0.19 2.5 1.6 1.3 0.15 0.20 A194 0.58 0.45 1.7 1.3 0.05 0.49 0.18 A196 1.1 0.44 9.7 1.9 5.9 1.8 0.86 A226 0.93 0.33 9.7 >3.3 1.6 0.73 <0.033 A234 0.89 0.25 3.8 2.5 1.0 0.26 0.32 A235 0.72 0.27 2.8 2.9 0.75 0.24 0.35 A237 1.1 0.40 >4 2.9 2.0 0.29 0.46 A258 0.62 0.23 4.9 >1.6 0.62 0.45 0.66 A285 0.69 0.2 3.1 1.9 0.68 0.18 0.46 A286 1.3 0.57 >5 1.4 0.87 0.23 0.61 A296 5.1 1.7 20 17 4.5 2.0 4.8 A303 1.4 0.83 6.5 3.6 1.4 0.97 1.9 A304 0.80 0.35 3.6 1.9 0.76 0.34 0.90 A306 0.83 0.49 2.9 2.1 0.89 0.73 0.88 A307 0.79 0.34 1.9 1.3 0.83 0.39 0.86 A308 0.87 0.31 3.9 1.6 0.81 0.36 0.94 A309 0.76 0.28 3.3 1.5 0.48 0.25 0.58 A311 0.67 0.42 3.3 2.0 1.0 0.53 1.2 A313 0.94 0.35 3.8 3.0 0.90 0.33 0.96 A314 0.60 0.51 1.5 0.82 0.56 0.55 0.38 A315 0.54 0.30 1.2 0.63 0.52 0.28 0.26 A316 0.78 0.39 1.2 1.1 0.56 0.29 0.27 A317 0.81 0.35 2.6 1.1 0.82 0.43 0.40 A318 0.47 0.27 2.0 0.65 0.45 0.38 0.16 A319 2.0 0.81 8.9 9.4 1.5 0.80 2.0 A320 >5 0.15 >5 >5 0.12 0.051 0.051 A321 NT NT NT NT 0.60 0.056 0.066 A322 NT NT NT NT 0.18 0.030 0.034 A323 >2 >2 >2 >2 0.27 0.038 0.011 A324 NT NT NT NT 0.53 0.12 0.046 A325 >2.5 >2.5 >2.5 >2.5 >2.5 0.066 0.022 A326 >2.5 >2.5 >2.5 >2.5 >2.5 0.48 0.067

TABLE V-1 in vitro Anti-picornavirus activity IC₅₀(μg/ml) polio Echo HRV HRV HRV HRV HRV Compd. 1 11 CA7 CB4 1A 1B 2 14 89 B2 0.58 0.19 3.1 0.97 5.0 0.54 0.15 0.65 0.48 B3 0.72 0.35 2.1 0.82 2.6 0.30 0.54 0.74 0.57 B7 0.42 0.25 1.4 0.52 1.7 0.17 0.36 0.49 0.30 B8 0.19 0.17 0.70 0.60 >1 0.24 0.22 0.40 0.12 B9 0.18 0.18 0.71 0.56 >1 0.25 0.20 0.58 0.21 B10 0.17 0.14 1.4 0.57 1.9 0.25 0.16 0.52 0.33 B11 0.45 0.28 >2 1.6 1.7 0.36 0.34 0.78 0.31 B12 0.39 0.19 2.0 0.63 >2.5 0.25 0.31 0.43 0.31 B15 0.49 0.27 2.2 1.9 >2.5 0.36 0.44 0.84 0.39 B20 0.40 0.28 1.4 0.60 >2.5 0.23 0.19 0.51 0.18 B22 0.54 0.39 1.9 1.3 >5.9 0.44 0.55 0.86 0.36

TABLE V-2 in vitro Anti-picornavirus activity IC₅₀(μg/ml) polio Echo HRV HRV HRV HRV HRV Compd. 1 11 CA7 CB4 1A 1B 2 14 89 C40 0.54 0.24 >3.3 1.7 >3.3 0.51 0.54 1.1 0.56 C43 1.5 0.54 >5 2.9 >5 1.5 0.67 2.5 0.86 C49 0.52 0.26 9.2 2.3 >10 1.9 1.7 5.5 2.1

TABLE V-3 in vitro Anti-picornavirus activity IC₅₀(μg/ml) polio Echo HRV HRV HRV HRV HRV Compd. 1 11 CA7 CB4 1A 1B 2 14 89 D50 0.64 0.27 1.9 0.82 2.2 0.25 0.20 1.3 0.41 D51 0.28 0.21 1.1 0.72 3.1 0.59 0.27 0.82 0.35 D52 1.0 0.55 >5 3.0 3.1 0.89 0.86 1.1 0.85 D53 1.8 0.68 >10 >3.3 >10 1.6 0.91 2.3 1.4

TABLE VI-1 Cytotoxicity CC₅₀(μg/ml) Compound HeLa-S3 HeLa HeLa(Ohio) A30 6.5 6.0 5.8 A32 >10 9.7 >10 A37 12 11 11 A60 7.0 5.3 5.7 A61 >4 >4 >4 A78 >8 >8 >8 A81 7.6 6.5 5.8 A97 >10 5.1 4.5 A98 >4 >4 >4 A99 5.8 5.4 5.7 A100 >5 >5 >5 A122 >10 >10 >10 A130 >4 >4 >4 A157 >5 >5 >5 A159 >5 >5 >5 A160 >5 >5 >5 A169 >50 >50 >50 A171 >2.5 >2.5 >2.5 A179 >4 >4 >4 A181 >2.5 >2.5 >2.5 A186 >5 >5 5.0 A187 >4 >4 >4 A188 >5 >5 >5 A190 >4 >4 >4 A191 >4 >4 >4 A194 >2.5 >2.5 >2.5 A196 >10 >10 >10 A226 >10 >10 >10 A234 >5 >5 >5 A235 >4 >4 >4 A237 >4 >4 >4 A258 >5 4.5 4.9 A285 >4 >4 >4 A286 >5 >5 >5 A296 >100 75 68 A303 >20 >20 >20 A304 >20 18 19 A306 26 14 25 A307 >20 >20 18 A308 16 11 11 A309 18 12 14 A311 >10 6.8 >10 A313 >20 18 15 A314 >10 7.0 >10 A315 >10 7.1 >10 A316 >5 >5 >5 A317 >5 >5 >5 A318 >2.5 >2.5 >2.5 A319 >50 35 32 A320 >5 >5 >5 A321 NT NT >1 A322 NT NT >1 A323 >2 >2 >2 A324 NT NT >1 A325 >2.5 >2.5 >2.5 A326 >2.5 >2.5 >2.5

TABLE VI-2 Cytotoxicity CC₅₀(μg/ml) Compound HeLa-S3 HeLa HeLa(Ohio) B2 >10 >10 >10 B3 >4 >4 >4 B7 >2.5 >2.5 >2.5 B8 >1 >1 >1 B9 >1 >1 >1 B10 >2.5 >2.5 >2.5 B11 >2 >2 >2 B12 >2.5 >2.5 >2.5 B15 >2.5 >2.5 >2.5 B20 >2.5 >2.5 >2.5 B22 >10 >10 >10

TABLE VI-3 Cytotoxicity CC₅₀(μg/ml) Compound HeLa-S3 HeLa HeLa(Ohio) D50 >10 7.8 >10 D51 >5 >5 >5 D52 >5 >5 >5 D53 >10 >10 >10

2. Anti-Rhinovirus Spectrum

In the above cell-based assays, some compounds demonstrate potent antiviral activities against 3 HRV serotypes tested. Therefore, we expanded our assessment of the antiviral activity of the compounds to a larger panel of HRV serotypes. HRV1A (E28), HRV3(FEB), HRV50, HRV8(MRH), HRV10 (204-CV14), HRV13 (353), HRV14 (1059), HRV16 (11757), HRV21 (47), HRV29 (5582), HRV31 (41F), HRV32 (363), HRV33 (1200) HRV36 (342H), HRV39 (209), HRV41 (56110), HRV50(A2#58), HRV61 (6669-CV39), and clinical isolate (89229T) were tested in the same method described above for sensitivity to the compounds. As shown in Table VII and VIII, some of the compounds exhibit potent activity against a broad spectrum of rhinovirus serotypes.

TABLE VII Anti-rhinovirus activity Rhinovirus Serotype Compd. A320 Compd. A322 Compd. A323 HRV1A >5.0 >1.0 >2.0 HRV1B 0.12 0.18 0.27 HRV2 0.051 0.030 0.038 HRV3 >5.0 >1.0 >2.0 HRV5 >5.0 >1.0 >2.0 HRV8 >5.0 >1.0 >2.0 HRV10 0.021 0.013 0.032 HRV13 0.23 0.029 0.12 HRV14 >5.0 >1.0 >2.0 HRV16 0.023 0.030 0.033 HRV21 0.024 0.048 0.067 HRV29 0.079 0.080 0.11 HRV31 0.046 0.045 0.088 HRV32 0.051 0.020 0.077 HRV33 0.23 0.17 0.30 HRV36 0.082 0.085 0.13 HRV39 <0.017 0.012 0.018 HRV41 0.066 0.034 0.058 HRV50 0.020 0.023 0.038 HRV61 0.21 0.29 0.30 HRV89 0.051 0.034 0.011 Clinically 0.017 0.017 0.030 isolated strain

TABLE VIII Anti-Rhinovirus activity Compd. Compd. Compd. Compd. Compd. Compd. Compd. Virus Compd. B3 B7 B9 B10 B12 B15 B20 B22 HRV1A 2.6 1.7 >1.0 1.9 >2.5 >2.5 >2.5 >5.9 HRV1B 0.30 0.20 0.25 0.25 0.25 0.36 0.23 0.44 HRV2 0.54 0.36 0.20 0.16 0.31 0.44 0.19 0.50 HRV3 2.9 0.49 0.23 0.48 0.52 1.1 0.50 0.97 HRV5 0.36 0.22 0.17 0.24 0.29 0.39 0.23 0.43 HRV8 0.46 0.32 0.15 0.20 0.32 0.38 0.29 0.46 HRV10 1.8 0.41 0.47 0.41 0.43 1.1 0.42 0.53 HRV13 0.17 0.13 0.14 0.12 0.091 0.18 0.13 0.13 HRV14 0.74 0.49 0.58 0.52 0.43 0.84 0.51 0.86 HRV16 2.3 0.98 0.47 0.57 1.4 1.2 0.44 1.2 HRV21 0.20 0.11 0.16 0.16 0.17 0.34 0.14 0.18 HRV29 1.5 0.43 0.19 0.44 0.44 0.67 0.44 0.56 HRV31 0.29 0.13 0.15 0.15 0.11 0.38 0.18 0.14 HRV32 0.61 0.30 0.13 0.36 0.33 0.65 0.29 0.19 HRV33 0.20 0.097 0.094 0.11 0.12 0.29 0.097 0.16 HRV36 0.30 0.16 0.16 0.17 0.21 0.32 0.20 0.25 HRV39 1.7 0.38 0.20 0.39 0.38 0.46 0.35 0.46 HRV41 0.20 0.064 0.13 0.007 0.11 0.18 0.12 0.14 HRV50 0.20 0.12 0.13 0.10 0.12 0.28 0.18 0.17 HRV61 0.80 0.28 0.16 0.24 0.31 0.39 0.31 0.34 HRV89 0.57 0.30 0.21 0.33 0.31 0.39 0.18 0.36 Clinical 1.9 0.50 0.31 0.75 0.46 1.1 0.49 0.43 isolated strain

3. In Vitro Anti-Rotavirus Activity

Human rotavirus (HROV, Odelia) and simian rotavirus (SRoV, SA11) were used in this experiment. Confluent monolayers of MA104 cells in 6-well multiplate were washed with Eagle MEM containing 0.5 μg/ml of trypsin and were infected with tripsinized-rotavirus (treated with 10 μg/ml of tripsin at 37° C. for 1.5 hr) at 50 PFU per well. After 1 hr of adsorption, the virus inoculum was removed, and the monolayers were washed with Eagle MEM containing 0.5 μg/ml of trypsin and overlaid with Eagle MEM containing 1 μg/ml of trypsin, 0.6% purified agar and the test compounds at various concentrations. The cultures were incubated at 37° C. for 3 days and same overlay medium was added. Four days after infection, the cell sheets were washed with PBS and stained with 1.3% crystal violet in 95% ethanol. The antiviral efficacy of the compounds was expressed as the IC₅₀, that is the concentration of the compounds required to reduce the number of plaques to 50% in the control (virus-infected, but not untreated).

The compounds tested specifically inhibited the multiplication of HRoV (Odelie) and SRoV (SA11) as shown in Table IX.

TABLE IX Anti-rotavirus activity IC₅₀(μg/mL) Compound HRoV(Odelia) SRoV(SA11) A323 1.30 0.90 B9 0.56 0.59 

1. A 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compound of Formula I:

wherein each R₁ is a member independently selected from the group consisting of alkyl, cycloalkyl, phenyl, alkoxy, cycloalkyloxy, phenoxy, methylenedioxy, trifluoromethyl, halogen, OH, NO₂, NH₂, mono- or dialkylamino, pyrrolidino, methylpiperazino, 4-acetylpiperazino, morpholino, pyridyl, pyridyloxy, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiomorpholino, dialkylaminoalkylamino, N-alkylaminoalkyl-N-alkylamino, N-hydroxyalkyl-N-alkylamino, dialkylamino alkoxy, acetoxy, hydroxycarbonyloxy, alkoxycarbonyloxy, hydroxycarbonylmethoxy and alkoxycarbonylmethoxy, and n is 1, 2 or 3; wherein R₂ is a member selected from the group consisting of alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thiazolyl, thienyl which may be optionally substituted with alkyl or halogen, and phenyl which may be optionally substituted with up to two substituents independently selected from the group consisting of halogen, OH, alkyl, alkoxy, trifluoromethyl and acetoxy; wherein R₃ is a member selected from the group consisting of hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN and acetyl; or if R₂ is a phenyl group optionally substituted with halo, alkyl or alkoxy groups, R₃ may represent a bridging group between the 3rd position of the quinoline ring and said phenyl group at a position next to the ring carbon atom at which said phenyl group is directly connected to the quinoline ring, said bridging group being selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, α-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene, α-alkoxybenzylidene, 1,2-ethylidene and 1,3-propylidene; or if R₂ is 2-thienyl, 4- or 5-alkyl-2-thienyl or N-alkylpyrrol-3-yl, R₃ may represent methylene bridge between the 3rd position of the quinoline ring and said thienyl group at the 3rd position or said pyrrolyl group at the 2nd position, and wherein R₄ is a member selected from the group consisting of alkyl, alkenyl, benzyl and phenyl optionally substituted with halo, alkyl or alkoxy.
 2. A compound according to claim 1 of Formula I-a:

wherein R₂′ is phenyl or substituted phenyl having up to two substituents independly selected from the group consisting of halo, OH, alkyl, alkoxy, trifluoromethyl and acetoxy; R₃′ is hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN or acetyl; and R₁, R₄ and n are as defined above.
 3. A compund according to claim 1 of Formula I-b:

wherein R₂″ is alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thienyl, substituted thienyl having up to two halo- or alkyl substituents, or thiazolyl; and R₁, R₃′, R₄ and n are as defined above.
 4. A compound according to claim 1 of Formula I-c:

wherein R₅ is a member independly selected from the group consisting of hydrogen, halo, alkyl and alkoxy; R₆ and R₇ together with the carbon atom to which they are attached represent a bridge selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, α-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene and α-alkoxybenzylidene; m is 1 or 2; and R₁, R₄ and n are as defined above.
 5. A compound according to claim 1 of Fomula I-d:

wherein R₁, R₄, R₅, n and m are as defined above.
 6. A compound according to claim 1 of Formula I-c:

wherein R₁, R₄, R₅, n and m are as defined above.
 7. A compound according to claim 1 of Formula I-f:

wherein R₈ is hydrogen or alkyl; and R₁, R₄ and n are as defined above. 